2-alkylbenzoxazole carboxamides as 5HT3 modulators

ABSTRACT

Compounds of formulae I and II: 
                         
are disclosed as 5-HT 3  inhibitors. Those compounds are useful in treating CINV, IBS-D and other diseases and conditions.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of application Ser. No. 11/834,909filed Aug. 7, 2007, which claims priority from U.S. ProvisionalApplication Ser. No. 60/821,650, filed Aug. 7, 2006. The entire contentof each prior application is hereby incorporated by reference.

FIELD OF THE INVENTION

The invention relates to a genus of 2-alkylbenzoxazole carboxamides thatare useful in treating chemotherapy-induced nausea and vomiting (CINV)and in treating diarrhea-predominant Irritable Bowel Syndrome (IBS-D).

BACKGROUND OF THE INVENTION

Nausea and vomiting caused by chemotherapy remain among the mostdistressing side effects for patients undergoing treatment for cancer.Depending upon the chemotherapy agents or regimens given, up to 90% ofpatients may suffer from some form of chemotherapy-induced nausea andvomiting (CINV). Symptoms from CINV can be severely debilitating andoften result in patients refusing further courses of chemotherapy, withobviously unfavorable consequences with respect to progression of thecancer. Furthermore, CINV is burdensome on the medical system, consumingtime from the healthcare staff, who could otherwise attend to otherpatients or medical issues.

CINV is divided into two main categories: acute CINV and delayed CINV.Acute CINV occurs within the first 24 hours of treatment; delayed CINVoccurs from 24 hours to 120 hours following treatment. Delayed CINVremains a highly under-treated side effect in patients undergoingchemotherapy, as healthcare providers tend to underestimate the numberof patients who suffer from delayed CINV. Furthermore, delayed CINVgreatly impairs patients' ability to provide care to themselves oncethey have been discharged.

Compounds that inhibit serotonin receptors are currently the mosteffective anti-emetics; they constitute the single greatest advance inthe management of nausea and vomiting in patients with cancer and havehad additional application in radiation-induced nausea and vomiting(RINV) and post-operative nausea and vomiting (PONV). Blocking the 5-HT₃receptor from the serotonin signal produced from chemotherapy-induceddamage to the gut's enterochromaffin cells, which house the majority ofthe body's serotonin reserves, via either a peripheral or centralmechanism appears to prevent acute emesis. Except for palonosetron(Aloxi®), 5-HT₃ inhibitors have been approved for and most effectiveagainst the treatment of acute CINV. Palonosetron, which must be givenintravenously, is the only 5-HT₃ inhibitor currently approved for theprevention of both acute and delayed CINV. The efficacy of palonosetronagainst delayed emesis has been postulated to be due to its long serumhalf-life. Therefore persons of skill in the art accept that 5-HT₃inhibitors that have long serum half-lives will be effective therapeuticagents for both acute and delayed CINV; those that have short half-liveswill be useful to treat acute CINV. In addition, the combination ofpalonosetron, a 5-HT₃ inhibitor, and aprepitant (EMEND®), a neurokininantagonist, has been shown to be highly effective in preventing bothacute and delayed CINV following a variety of moderately to highlyemetogenic chemotherapy regimens in clinical trials. Notably,combination therapy of either NK1 antagonists or 5-HT₃ antagonists withcorticosteroids such as dexamethasone, improve the performance of thesedrugs against acute or delayed emesis. To that point, EMEND® labelingindicates that the drug is dosed with a corticosteroid and a 5-HT₃antagonist.

Irritable Bowel Syndrome (IBS) generally occurs in three types: diarrheapredominant (IBS-D), constipation predominant (IBS-C) and IBS withalternating symptoms termed IBS-A or mixed-mode (IBS-M). Diarrheapredominant Irritable Bowel Syndrome is a debilitating, though seldomfatal, disease. The typical sufferer of IBS-D exhibits primary symptomsincluding multiple and daily explosive diarrhea attacks and severe dailyabdominal cramps. The most common secondary side effects include panicattacks, depression, withdrawal from social and family activities andmalnutrition.

At present, compounds that inhibit 5-HT₃ receptors are the onlyeffective treatment for IBS-D. The only drug currently approved forIBS-D is alosetron, which was introduced by Glaxo, withdrawn by the FDAbecause it appeared to cause ischemic colitis, then reinstated by theFDA because the demand was so great for some treatment for IBS-D. In2002, the US Food and Drug Administration approved alosetronhydrochloride (LOTRONEX®) tablets under restricted conditions for womenin whom the medical benefits outweigh the risks. The restrictions on theapproval reflect the serious gastrointestinal adverse events that havebeen reported with the use of alosetron. A second structurally related5-HT₃ inhibitor, cilansetron, had been making its way through clinicaltrials and recently received a non-approvable letter from the FDA. New,structurally unrelated 5-HT₃ inhibitors may be useful for the treatmentof IBS-D.

Clearly there is a need for improved therapy for both CINV and IBS-D.

SUMMARY OF THE INVENTION

It has now been found that certain benzoxazoles of the general formula

are potent and selective inhibitors of the 5-HT₃ receptor. In thesecompounds R¹, R² and R³ are independently selected from hydrogen,halogen, amino, alkylamino, dialkylamino, acylamino, morpholinyl,—O-loweralkyl, hydroxy, loweralkyl, fluoroloweralkyl,—O-lowerfluoroalkyl, methylenedioxy, ethylenedioxy, alkoxy-loweralkyland hydroxyloweralkyl;R⁴ is a residue chosen from:(i) a saturated nitrogen heterocycle or methyl-substituted saturatednitrogen heterocycle, in which said nitrogen is tertiary, saidheterocycle containing at least one 5 or 6-membered ring; and(ii) an imidazolylalkyl residue wherein the imidazole of saidimidazolylalkyl is optionally substituted with up to three groups chosenfrom halogen, (C₁-C₄)alkyl, substituted (C₁-C₄)alkyl and NH₂; andR¹⁰ is chosen from the group consisting of(i) hydrogen;(ii) (C₁-C₁₀)alkyl;(iii) substituted (C₁-C₁₀)alkyl;(iv) saturated C-attached heterocyclyl; and(v) substituted, saturated C-attached heterocyclyl.

In another aspect, the invention relates to pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound of formula I or II. The compositions maycomprise an additional antiemetic agent, particularly a neurokininantagonist. The compositions may also include a corticosteroid.

In another aspect, the invention relates to a method of treating adisorder arising from inappropriate activity of the serotonin type 3receptor or dependent upon modulation of the serotonin type 3 receptor.The method comprises administering a therapeutically effective amount ofa compound of formula I or II. Exemplary disorders arising frominappropriate activity of the serotonin type 3 receptor or dependentupon modulation of the serotonin type 3 receptor include emesis,particularly CINV, and IBS-D. Other such disorders include psychologicaldisorders, obesity, substance abuse disorders, dementia associated witha neurodegenerative disease, cognition loss, pain, fibromyalgia syndromeand chronic fatigue syndrome (see US published application2004/0204467). Serotonin type 3 receptor antagonists are also known tobe useful for the prevention and treatment of bronchial asthma, bulimianervosa, sleep apnea, pruritis and migraine (see Costall and Naylor,Current Drug Targets—CNS & Neurological Disorders, 2004:3 27-37 andIsraili, Current Med. Chem.—CNS Agents, 2001:1 171-199.). Serotonin type3 receptor antagonists are also known to be useful for the preventionand treatment of epilepsy. Application of such compounds for thetreatment of epilepsy has been demonstrated in International ApplicationNumber PCT/GB2006/002733.

DETAILED DESCRIPTION OF THE INVENTION

Throughout this specification the substituents are defined whenintroduced and retain their definitions.

Benzoxazoles of the general formula

are potent and selective inhibitors of the 5-HT₃ receptor. The genus maybe divided into two subgenera, the 4-carboxamides (I) and the7-carboxamides (II):

In a first aspect the invention relates to compounds of formula I andII. In some embodiments, R⁴ is

and m is 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; Q is N(CH₃) or —O—; and R⁵is hydrogen or methyl. For example, R⁴ may be quinuclidine, tropane,azabicyclo[3.3.1]nonane, methyl azabicyclo[3.3.1]nonane or dimethyldiazabicyclo[3.3.1]nonane.

In some embodiments, R¹, R² and R³ are hydrogen; in others one of R¹,R², and R³ is halogen.

In some embodiments, R¹⁰ is chosen from the group consisting of hydrogenand (C₁ to C₃)alkyl. In other embodiments, R¹⁰ is chosen from the groupconsisting of (C₄ to C₁₀)alkyl and substituted (C₁-C₁₀)alkyl. Examplesof such embodiments are those in which R¹⁰ is chosen from

In other embodiments, R¹⁰ is chosen from the group consisting ofsaturated, C-attached, nitrogenous heterocyclyl; and substituted,saturated, C-attached, nitrogenous heterocyclyl. Examples include

In other embodiments, R¹⁰ is chosen from the group consisting ofsaturated, C-attached, oxygen heterocyclyl; and substituted, saturated,C-attached, oxygen heterocyclyl, for example, tetrahydropyran-4-yl.

Compounds falling within the foregoing parent genus and its subgeneraare useful as 5-HT₃ inhibitors. It may be found upon examination thatcompounds that are not presently excluded from the claims are notpatentable to the inventors in this application. In that case, theexclusion of species and genera in applicants' claims are to beconsidered artifacts of patent prosecution and not reflective of theinventors' concept or description of their invention. The invention, ina composition aspect, is all compounds of formulae I and II, exceptthose that are in the public's possession.

DEFINITIONS

Alkyl is intended to include linear, branched, or cyclic hydrocarbonstructures and combinations thereof. Lower alkyl refers to alkyl groupsof from 1 to 6 carbon atoms. Examples of lower alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl and the like.Preferred alkyl groups are those of C₂₀ or below. Cycloalkyl is a subsetof alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbonatoms. Examples of cycloalkyl groups include c-propyl, c-butyl,c-pentyl, norbornyl and the like. Certain moieties require explicitmention. The statement that alkyl is intended to include linear,branched, or cyclic hydrocarbon structures and combinations thereofmeans that the following combination of linear and cyclic structuralelements (and similar combinations)

is considered an “alkyl” group. C₁ to C₂₀ hydrocarbon includes alkyl,cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examplesinclude phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl.

Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of astraight, branched, cyclic configuration and combinations thereofattached to the parent structure through an oxygen. Examples includemethoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy andthe like. Lower-alkoxy refers to groups containing one to four carbons.

Oxaalkyl refers to alkyl residues in which one or more carbons has beenreplaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyland the like.

Acyl refers to groups of from 1 to 8 carbon atoms of a straight,branched, cyclic configuration, saturated, unsaturated and aromatic andcombinations thereof, attached to the parent structure through acarbonyl functionality. One or more carbons in the acyl residue may bereplaced by nitrogen, oxygen or sulfur as long as the point ofattachment to the parent remains at the carbonyl. Examples includeacetyl (Ac), benzoyl, propionyl, isobutyryl, t-butoxycarbonyl,benzyloxycarbonyl and the like. Lower-acyl refers to groups containingone to four carbons.

Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromaticring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9-or 10-membered aromatic or heteroaromatic ring system containing 0-3heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-memberedaromatic or heteroaromatic ring system containing 0-3 heteroatomsselected from O, N, or S. The aromatic 6- to 14-membered carbocyclicrings include, e.g., benzene, naphthalene, indane, tetralin, andfluorene and the 5- to 10-membered aromatic heterocyclic rings include,e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole,furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine,pyrazine, tetrazole and pyrazole.

Arylalkyl refers to a residue in which an aryl moiety is attached to theparent through an alkyl. Examples are benzyl, phenethyl and the like.Tolyl is not arylalkyl; tolyl is alkylaryl. Heteroarylalkyl means aheteroaryl residue attached to the parent via alkyl. Examples include,e.g., pyridinylmethyl, pyrimidinylethyl and the like.

Heterocycle means a cycloalkyl or aryl residue in which from one tothree carbons is replaced by a heteroatom selected from the groupconsisting of N, O and S. The nitrogen and sulfur heteroatoms mayoptionally be oxidized, and the nitrogen heteroatom may optionally bequaternized. Examples of heterocycles include pyrrolidine, pyrazole,pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline,benzofuran, benzodioxan, benzodioxole (commonly referred to asmethylenedioxyphenyl, when occurring as a substituent), tetrazole,morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene,furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and thelike. Nitrogen heterocycles are heterocycles containing at least onenitrogen. They may additionally include other heteroatoms and multiplenitrogens. Examples include quinuclidine, tropane, piperidine,piperazine, morpholine, quinoline and thiazole. It is to be noted thatheteroaryl is a subset of heterocycle in which the heterocycle isaromatic. Dihydroheteroaryl are, as the name implies, heteraryl residuesformally reduced by one mole of hydrogen. An example of adihydroheteroaryl residue is 2,3-dihydrobenzofuran.

Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl,aryl, cycloalkyl, or heterocyclyl wherein up to four H atoms in eachresidue are replaced with halogen, haloalkyl, hydroxy, loweralkoxy,carboxy, alkoxycarbonyl (COOR), carboxamido (—CONR₂), sulfonamido(—SO₂NR₂), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino,mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl,benzyl, heteroaryl, heterocyclyl; phenoxy, benzyloxy, or heteroaryloxy.In the foregoing listing, R is hydrogen or alkyl.

The term “halogen” means fluorine, chlorine, bromine or iodine.

Some of the compounds described herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-. The present invention is meant toinclude all such possible isomers, as well as, their racemic andoptically pure forms. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms are alsointended to be included. The configuration of any carbon-carbon doublebond appearing herein is selected for convenience only and is notintended to designate a particular configuration; thus a carbon-carbondouble bond depicted arbitrarily herein as trans may be Z, E or amixture of the two in any proportion.

It will be recognized that the compounds of this invention can exist inradiolabeled form, i.e., the compounds may contain one or more atomscontaining an atomic mass or mass number different from the atomic massor mass number usually found in nature. Radioisotopes of hydrogen,carbon, phosphorous, fluorine, chlorine and iodine include ³H, ¹⁴C, ³⁵S,¹⁸F, ³⁶Cl and ¹²⁵I, respectively. Compounds that contain thoseradioisotopes and/or other radioisotopes of other atoms are within thescope of this invention. Tritiated, i.e. ³H, and carbon-14, i.e., ¹⁴C,radioisotopes are particularly preferred for their ease in preparationand detectability. Radiolabeled compounds of this invention cangenerally be prepared by methods well known to those skilled in the art.Conveniently, such radiolabeled compounds can be prepared by carryingout the procedures disclosed in the Examples and Schemes by substitutinga readily available radiolabeled reagent for a non-radiolabeled reagent.

The compounds of the invention may be conveniently divided into twosubgenera, the benzoxazole-4-carboxamides I and thebenzoxazole-7-carboxamides II:

In these compounds, R⁴ represents a saturated nitrogen heterocycle ormethyl-substituted saturated nitrogen heterocycle, in which the nitrogenis tertiary. A nitrogen heterocycle (also referred to as a nitrogenousheterocycle) is a heterocycle containing at least one nitrogen in thering; it may contain additional nitrogens, as well as other heteroatoms.Nitrogenous heterocycles include piperidine, methylpiperidine,quinuclidine, tropane, azabicyclo[3.3.1]nonane, methylazabicyclo[3.3.1]nonane, 9-azabicyclo[3.3.1]nonan-3-one, and

in which X is NCH₃, O, S, SO or SO₂.

Terminology related to “protecting”, “deprotecting” and “protected”functionalities occurs throughout this application. Such terminology iswell understood by persons of skill in the art and is used in thecontext of processes which involve sequential treatment with a series ofreagents. In that context, a protecting group refers to a group which isused to mask a functionality during a process step in which it wouldotherwise react, but in which reaction is undesirable. The protectinggroup prevents reaction at that step, but may be subsequently removed toexpose the original functionality. The removal or “deprotection” occursafter the completion of the reaction or reactions in which thefunctionality would interfere. Thus, when a sequence of reagents isspecified, as it is in the processes of the invention, the person ofordinary skill can readily envision those groups that would be suitableas “protecting groups”. Suitable groups for that purpose are discussedin standard textbooks in the field of chemistry, such as ProtectiveGroups in Organic Synthesis by T. W. Greene [John Wiley & Sons, NewYork, 1991], which is incorporated herein by reference.

A comprehensive list of abbreviations utilized by organic chemistsappears in the first issue of each volume of the Journal of OrganicChemistry. The list, which is typically presented in a table entitled“Standard List of Abbreviations” is incorporated herein by reference.

Generalized synthetic schemes are presented below:

EXAMPLES

Exemplary syntheses are provided below.

Example 1 Preparation ofEndo-N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-cyclopropylbenzoxazole-4-carboxamide

Step A: To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (0.25g, 1.07 mmol) and cyclopropanecarbonyl chloride (0.10 mL, 1.07 mmol) indichloromethane (8 mL) was added triethylamine (0.60 mL, 4.28 mmol)dropwise, then the reaction mixture was stirred at room temperature for12 h. The reaction mixture was diluted with dichloromethane, and thenwashed with 2 N HCl. The aqueous layer was extracted withdichloromethane. The combined organic layers were washed with brine,dried (Na₂SO₄), filtered and concentrated. The crude product wasdissolved in toluene (8 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (204 mg, 1.07 mmol). The reactionmixture was then heated to reflux for 5 h. The reaction was cooled toroom temperature, poured into water and extracted with ethyl acetate.The organic layer was separated then washed with water, brine, dried(Na₂SO₄), filtered and concentrated. The crude product was purified bycolumn chromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) toafford 2-cyclopropylbenzoxazole-4-carboxylic acid (0.14 g, 65%) as awhite solid: ¹H NMR (500 MHz, DMSO-d₆) δ 12.92 (br s, 1H), 7.85 (dd,J=8.0, 0.6 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H),2.37-2.31 (m, 1H), 1.26-1.16 (m, 4H); MS (ESI+) m/z 204 (M+H).

Step B: A mixture of 2-cyclopropylbenzoxazole-4-carboxylic acid fromStep A (65 mg, 0.32 mmol),endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (73 mg,0.32 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(123 mg, 0.64 mmol) and 1-hydroxybenzotriazole (86 mg, 0.64 mmol) in DMF(2 mL) was stirred at room temperature for 5 min, then triethylamine(0.17 mL, 1.28 mmol) was added. The resulting reaction mixture wasstirred at room temperature for 12 h. The mixture was diluted withdichloromethane (20 mL), then washed with a saturated solution of sodiumbicarbonate (10 mL). The aqueous layer was further extracted withdichloromethane (3×15 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 89:10:1dichloromethane/methanol/concentrated ammonium hydroxide) to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-cyclopropylbenzoxazole-4-carboxamide(45 mg, 41%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.91 (d, J=6.0Hz, 1H), 8.12 (dd, J=8.0, 1.0 Hz, 1H), 7.53 (dd, J=8.0, 1.0 Hz, 1H),7.39 (t, J=8.0 Hz, 1H), 4.57-4.51 (m, 1H), 3.09 (d, J=10.5 Hz, 2H),2.61-2.55 (m, 2H), 2.53 (s, 3H), 2.35-2.25 (m, 1H), 2.12-1.95 (m, 3H),1.60-1.40 (m, 3H), 1.45-1.22 (m, 4H), 1.12 (d, J=12.5 Hz, 2H); MS (ESI+)m/z 340 (M+H); HPLC >99% (AUC), t_(R)=12.12 min.

Example 2 Preparation of(S)—N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylbenzoxazole-4-carboxamide

A mixture of 2-cyclopropylbenzoxazole-4-carboxylic acid (65 mg, 0.32mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (64 mg, 0.32 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (123 mg,0.64 mmol) and 1-hydroxybenzotriazole (86 mg, 0.64 mmol) in DMF (2 mL)was stirred at room temperature for 5 min, then triethylamine (0.17 mL,1.28 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 12 h. The mixture was diluted with dichloromethane (20mL), then washed with a saturated solution of sodium bicarbonate (10mL). The aqueous layer was further extracted with dichloromethane (3×15mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 89:10:1 dichloromethane/methanol/concentrated ammoniumhydroxide) to afford(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylbenzoxazole-4-carboxamide(43 mg, 43%) as a colorless semisolid: ¹H NMR (500 MHz, CDCl₃) δ 9.43(d, J=7.0 Hz, 1H), 8.10 (dd, J=7.5, 1.0 Hz, 1H), 7.56 (dd, J=8.0, 2.0Hz, 1H), 7.36 (t, J=8.5 Hz, 1H), 4.28-4.22 (m, 1H), 3.49 (ddd, J=11.5,9.5, 2.0 Hz, 1H), 3.10-2.85 (m, 4H), 2.75 (dd, J=14.0, 4.5 Hz, 1H),2.28-2.20 (m, 1H), 2.12-2.06 (m, 1H), 2.00-1.90 (m, 1H), 1.75-1.69 (m,2H), 1.60-1.50 (m, 1H), 1.35-1.22 (m, 4H); MS (ESI+) m/z 312 (M+H);HPLC >99% (AUC), t_(R)=12.31 min.

Example 3 Preparation ofEndo-N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-tert-butylbenzoxazole-4-carboxamide

Step A: To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (0.30g, 1.28 mmol) and pivaloyl chloride (0.16 mL, 1.28 mmol) indichloromethane (10 mL) was added triethylamine (0.72 mL, 5.12 mmol)dropwise, then the reaction mixture was stirred at room temperature for1 h. The reaction mixture was diluted with dichloromethane, and thenwashed with 2 N HCl. The aqueous layer was extracted withdichloromethane. The combined organic layers were washed with brine,dried (Na₂SO₄), filtered and concentrated. The crude product wasdissolved in toluene (10 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (240 mg, 1.26 mmol). The reactionmixture was then heated to reflux for 1.5 h. The reaction was cooled toroom temperature, poured into water and extracted with ethyl acetate.The organic layer was separated then washed with water, brine, dried(Na₂SO₄), filtered and concentrated. The crude product was purified bycolumn chromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) toafford 2-tert-butylbenzoxazole-4-carboxylic acid (0.15 g, 53%) as awhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.75-7.71 (m, 2H), 7.33 (t,J=7.8 Hz, 1H), 1.45 (s, 9H); MS (ESI+) m/z 220 (M+H).

Step B: A mixture of 2-tert-butylbenzoxazole-4-carboxylic acid from StepA (70 mg, 0.32 mmol), endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (73 mg, 0.32 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (123 mg,0.64 mmol) and 1-hydroxybenzotriazole (86 mg, 0.64 mmol) in DMF (1.5 mL)was stirred at room temperature for 5 min, then triethylamine (0.17 mL,1.28 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 12 h. The mixture was diluted with dichloromethane (20mL), then washed with a saturated solution of sodium bicarbonate (10mL). The aqueous layer was further extracted with dichloromethane (3×15mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 89:10:1 dichloromethane/methanol/concentrated ammoniumhydroxide) to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-tert-butylbenzoxazole-4-carboxamide(89 mg, 78%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.10 (d, J=7.5Hz, 1H), 8.14 (dd, J=8.0, 1.0 Hz, 1H), 7.59 (dd, J=7.5, 1.5 Hz, 1H),7.39 (t, J=8.0 Hz, 1H), 4.56-4.50 (m, 1H), 3.08 (d, J=10.5 Hz, 2H),2.65-2.58 (m, 2H), 2.53 (s, 3H), 2.10-1.95 (m, 3H), 1.60-1.52 (m, 1H),1.52 (s, 9H), 1.47-1.40 (m, 2H), 1.15 (d, J=12.5 Hz, 2H); MS (ESI+) m/z356 (M+H); HPLC >99% (AUC), t_(R)=12.89 min.

Example 4 Preparation of(S)—N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-tert-butylbenzoxazole-4-carboxamide

A mixture of 2-tert-butylbenzoxazole-4-carboxylic acid (70 mg, 0.32mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (64 mg, 0.32 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (123 mg,0.64 mmol) and 1-hydroxybenzotriazole (86 mg, 0.64 mmol) in DMF (1.5 mL)was stirred at room temperature for 5 min, then triethylamine (0.17 mL,1.28 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 12 h. The mixture was diluted with dichloromethane (20mL), then washed with a saturated solution of sodium bicarbonate (10mL). The aqueous layer was further extracted with dichloromethane (3×15mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 89:10:1 dichloromethane/methanol/concentrated ammoniumhydroxide) to afford(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-tert-butylbenzoxazole-4-carboxamide(68 mg, 65%) as a colorless semi-solid: ¹H NMR (500 MHz, CDCl₃) δ 9.60(d, J=7.5 Hz, 1H), 8.13 (dd, J=7.5, 1.0 Hz, 1H), 7.62 (dd, J=8.0, 2.0Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 4.32-4.26 (m, 1H), 3.47 (ddd, J=11.5,9.5, 2.0 Hz, 1H), 3.06-2.83 (m, 4H), 2.75 (dd, J=14.0, 4.5 Hz, 1H),2.10-1.95 (m, 2H), 1.76-1.70 (m, 2H), 1.60-1.54 (m, 1H), 1.52 (s, 9H);MS (ESI+) m/z 328 (M+H); HPLC >99% (AUC), t_(R)=11.84 min.

Example 5 Preparation ofEndo-N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-cyclopentylbenzoxazole-4-carboxamideHydrochloride

Step A: To a suspension of 2-amino-3-hydroxybenzoic acid hydrobromide(300 mg, 1.28 mmol) in dichloromethane (8 mL) was added cyclopentanecarbonyl chloride (0.16 mL, 1.28 mmol). The resulting reaction mixturewas stirred at room temperature for 10 min, then triethylamine (0.71 mL,5.13 mmol) was added and the reaction mixture was stirred at roomtemperature overnight. The reaction was diluted in dichloromethane (30mL) and quenched with aqueous 2 N HCl (10 mL) until the solution reachedpH 1. The aqueous layer was further extracted with dichloromethane (2×30mL). The organic layers were washed with water and brine, dried overNa₂SO₄, filtered and concentrated to an orange solid. The amide productwas directly re-dissolved in toluene (8 mL) and the solution was treatedwith p-toluenesulfonic acid monohydrate (296 mg, 1.56 mmol). Thereaction mixture was then heated to reflux for 3 h. The reaction wascooled to room temperature and the toluene was evaporated. The reactionmixture was poured into water and extracted with ethyl acetate. Theorganic layer was separated, washed with water, brine, dried overNa₂SO₄, filtered and concentrated. The crude product was purified bycolumn chromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) toafford 2-cyclopentylbenzoxazole-4-carboxylic acid (179 mg, 75%) as apale orange solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.85-7.72 (m, 2H),7.39-7.29 (m, 1H), 2.05-1.50 (m, 9H); MS (ESI+) m/z 232 (M+H).

Step B: A mixture of 2-cyclopentylbenzoxazole-4-carboxylic acid (85 mg,0.37 mmol), endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (100 mg, 0.44 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (142 mg,0.74 mmol) and 1-hydroxybenzotriazole (100 mg, 0.74 mmol) in DMF (2.5mL) was stirred for 10 min at room temperature, then triethylamine (0.26mL, 1.85 mmol) was added. The resulting reaction mixture was stirred atroom temperature overnight. The mixture was diluted with dichloromethane(30 mL), and then washed with a saturated solution of sodiumbicarbonate. The aqueous layer was further extracted withdichloromethane (2×30 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentratedammonium hydroxide) and semi-preparative HPLC to afford the free base asa white solid. The free base was dissolved in anhydrous ethyl ether (3mL). HCl solution (1 M in ether, 0.3 mL, 0.3 mmol) was added. A whiteprecipitate was formed and the mixture was diluted with ethyl ether andleft to stand overnight. The solution was decanted off and the solid wasdried under high vacuum to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-cyclopentylbenzoxazole-4-carboxamidehydrochloride (46 mg, 75%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ12.23 (br s, 0.5H), 11.83 (br s, 0.5H), 9.50 (d, J=6.0 Hz, 0.5H), 9.38(d, J=5.0 Hz, 0.5H), 8.12 (dd, J=7.5, 1.0 Hz, 1H), 8.09 (dd, J=8.0, 0.5Hz, 1H), 7.66 (dd, J=8.5, 1.0 Hz, 1H), 7.62 (dd, J=8.0, 0.5 Hz, 1H),7.46-7.38 (m, 2H), 4.77-4.69 (m, 0.5H), 4.59-4.52 (m, 0.5H), 3.50-3.49(m, 1H), 2.95-2.82 (m, 5H), 2.62-2.55 (m, 1H), 2.25-1.62 (m, 14H); MS(ESI+) m/z 368 (M+H); HPLC 96.4% (AUC), t_(R)=12.40 min.

Example 6 Preparation of(S)—N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-cyclopentylbenzoxazole-4-carboxamideHydrochloride

A mixture of 2-cyclopentylbenzoxazole-4-carboxylic acid (85 mg, 0.37mmol), (S)-3-aminoquinuclidine dihydrochloride (88 mg, 0.44 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (142 mg,0.74 mmol) and 1-hydroxybenzotriazole (100 mg, 0.74 mmol) in DMF (2.5mL) was stirred at room temperature for 10 min, then triethylamine (0.26mL, 1.85 mmol) was added. The resulting reaction mixture was stirred atroom temperature overnight. The mixture was diluted with dichloromethane(30 mL), and then washed with a saturated solution of sodiumbicarbonate. The aqueous layer was further extracted withdichloromethane (2×30 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentratedammonium hydroxide) and semi-preparative HPLC to afford the free base(17 mg, 14%) as an oil. The free base was dissolved in anhydrous ethylether (0.8 mL) and dichloromethane (0.3 mL). HCl solution (1 M in ether,0.1 mL, 0.1 mmol) was added. A white precipitate was formed and themixture was diluted with ethyl ether and left to stand overnight. Thesolution was decanted off and the solid was dried under high vacuum toafford(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopentylbenzoxazole-4-carboxamidehydrochloride (13 mg, 74%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ12.47 (br s, 1H), 9.62 (d, J=6.5 Hz, 1H), 8.09 (dd, J=8.0, 1.0 Hz, 1H),7.66 (dd, J=8.0, 0.5 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 4.68-4.62 (m, 1H),3.80 (t, J=10.5 Hz, 1H), 3.39-3.28 (m, 1H), 3.23-3.16 (m, 1H), 2.85 (d,J=5.0 Hz, 1H), 2.48 (s, 1H), 2.38-2.29 (m, 1H), 2.27-2.18 (m, 2H),2.15-2.07 (m, 2H), 2.06-1.96 (m, 4H), 1.95-1.75 (m, 6H); MS (ESI+) m/z340 (M+H); HPLC 98.4% (AUC), t_(R)=11.94 min.

Example 7 Preparation ofEndo-N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(1-methylcyclopropyl)benzoxazole-4-carboxamideHydrochloride

Step A: To an ice-cold solution of 1-methylcyclopropanecarboxylic acid(214 mg, 2.14 mmol) in dichloromethane (10 mL) was added oxalyl chloride(0.19 mL, 2.14 mmol) dropwise. The ice bath was removed and stirring wascontinued for 1 h. 2-Amino-3-hydroxybenzoic acid hydrobromide (500 mg,2.14 mmol) was added followed by triethylamine (0.90 mL, 6.42 mmol). Theresulting reaction mixture was stirred at room temperature overnight.The reaction was quenched with aqueous 1 N HCl (25 mL) until thesolution reached pH 1. The reaction mixture was extracted withdichloromethane. The combined organic layers were dried over Na₂SO₄,filtered and concentrated to a brown solid. The crude was dissolved intoluene (10 mL) and the solution was treated with p-toluenesulfonic acidmonohydrate (477 mg, 2.50 mmol). The reaction mixture was then heated toreflux for 1 h. The reaction was cooled to room temperature, poured intowater and extracted with ethyl acetate. The organic layer was separated,then washed with water (5×50 mL), brine, dried (Na₂SO₄), filtered andconcentrated to afford 2-(1-methylcyclopropyl)benzoxazole-4-carboxylicacid (306 mg, 65%) as a light yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ12.89 (br s, 1H), 7.85 (dd, J=8.0, 0.9 Hz, 1H), 7.81 (dd, J=7.7, 0.9 Hz,1H), 7.39 (t, J=7.9 Hz, 1H), 2.91 (s, 3H), 1.42-1.37 (m, 2H), 1.10-1.05(m, 2H); MS (ESI+) m/z 218 (M+H).

Step B: A mixture of 2-(1-methylcyclopropyl)benzoxazole-4-carboxylicacid (60 mg, 0.27 mmol), endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (77 mg, 0.34 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (103 mg,0.54 mmol) and 1-hydroxybenzotriazole (73 mg, 0.54 mmol) in DMF (2 mL)was stirred at room temperature for 5 min, then triethylamine (0.11 mL,0.81 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 12 h. The mixture was diluted with dichloromethane (20mL), and then washed with a saturated solution of sodium bicarbonate (10mL). The aqueous layer was further extracted with dichloromethane (3×15mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:9:1 dichloromethane/methanol/concentrated ammoniumhydroxide) to afford the carboxamide (69 mg, 79%) as a light brownsolid: ¹H NMR (500 MHz, CDCl₃) δ 8.95 (d, J=6.4 Hz, H), 8.11 (dd, J=7.8,1.0 Hz, 1H), 7.51 (dd, J=8.0, 0.9 Hz, H), 7.32 (t, J=7.9 Hz, 1H),4.50-4.40 (m, 1H), 3.20-3.10 (m, 2H), 2.65-2.57 (m, 2H), 2.56 (s, 3H),2.15-1.95 (m, 4H), 1.75-1.65 (m, 1H), 1.60-1.40 (m, 4H), 1.30-1.24 (m,3H), 1.20-1.15 (m, 2H), 1.09-1.05 (m, 1H); MS (ESI+) m/z 354 (M+H).

Step C: To a solution ofendo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1-methylcyclopropyl)benzoxazole-4-carboxamide(64 mg, 0.18 mmol) in methanol (2.0 mL) was added a solution of HCl indiethyl ether (1 N, 0.36 mL, 0.36 mmol) at 0° C. slowly. The reactionmixture was diluted with diethyl ether. The resulting solid was filteredand washed with diethyl ether to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(1-methylcyclopropyl)benzoxazole-4-carboxamidehydrochloride (67 mg, 95%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ9.98 (br s, 0.3H), 9.44 (br s, 0.7H), 9.18 (d, J=6.8 Hz, 0.3H), 8.96 (d,J=6.8 Hz, 0.7H), 7.95-7.88 (m, 2H), 7.50-7.42 (m, 1H), 4.55-4.50 (m,0.7H), 4.38-4.32 (m, 0.3H), 3.68-3.62 (m, 1.3H), 3.59-3.52 (m, 0.7H),2.88-2.82 (m, 3H), 2.75-2.60 (m, 2H), 2.35-2.10 (m, 3H), 1.82-1.70 (m,3H), 1.60-1.42 (m, 7H), 1.20-1.14 (m, 2H); MS (ESI+) m/z 354 (M+H);HPLC >99% (AUC), t_(R)=12.08 min.

Example 8 Preparation of(S)—N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(1-methylcyclopropyl)benzoxazole-4-carboxamideHydrochloride

Step A: A mixture of 2-(1-methylcyclopropyl)benzoxazole-4-carboxylicacid (60 mg, 0.27 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (67mg, 0.34 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (103 mg, 0.54 mmol) and 1-hydroxybenzotriazole (73 mg,0.54 mmol) in DMF (2 mL) was stirred at room temperature for 5 min, thentriethylamine (0.11 mL, 0.81 mmol) was added. The resulting reactionmixture was stirred at room temperature for 12 h. The mixture wasdiluted with dichloromethane (20 mL), then washed with a saturatedsolution of sodium bicarbonate (10 mL). The aqueous layer was furtherextracted with dichloromethane (3×15 mL). The combined organics weredried (Na₂SO₄), filtered and concentrated. The crude material waspurified by column chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(1-methylcyclopropyl)benzoxazole-4-carboxamide(69 mg, 79%) as a light brown semi-solid: ¹H NMR (500 MHz, CDCl₃) δ 9.61(d, J=7.3 Hz, 1H), 8.10 (dd, J=7.8, 1.0 Hz, 1H), 7.55 (dd, J=8.0, 0.9Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 4.34-4.28 (m, 1H), 3.55 (m, 1H),3.10-3.00 (m, 2H), 2.96-2.88 (m, 2H), 2.82-2.74 (m, 1H), 2.12-2.02 (m,2H), 1.80-1.75 (m, 2H), 1.65 (s, 3H), 1.64-1.57 (m, 1H), 1.52-1.48 (m,2H), 1.10-1.05 (m, 2H); MS (ESI+) m/z 326 (M+H).

Step B: To a solution of(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(1-methylcyclopropyl)benzoxazole-4-carboxamide(63 mg, 0.19 mmol) in methanol (2 mL) was added a solution of HCl indiethyl ether (1 N, 0.38 mL, 0.38 mmol) at room temperature slowly. Thereaction mixture was diluted with diethyl ether. The resulting solid wasfiltered and washed with diethyl ether to afford(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(1-methylcyclopropyl)benzoxazole-4-carboxamidehydrochloride (60 mg, 88%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ10.22 (br s, 1H), 9.36 (d, J=6.6 Hz, 1H), 8.10 (d, J=8.0 Hz, 2H), 7.46(t, J=7.9 Hz, 1H), 4.45-4.36 (m, 1H), 3.77-3.70 (m, 1H), 3.35-3.26 (m,2H), 3.24 (t, J=7.9 Hz, 2H), 3.17 (dd, J=13.2, 3.7 Hz, 1H), 2.30-2.15(m, 2H), 2.00-1.90 (m, 3H), 1.61 (s, 3H), 1.48-1.40 (m, 2H), 1.20-1.15(m, 2H); MS (ESI+) m/z 326 (M+H); HPLC >99% (AUC), t_(R)=11.65 min.

Example 9 Preparation ofEndo-N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-benzylbenzoxazole-4-carboxamideHydrochloride

Step A: To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (0.5g, 2.14 mmol) and triethylamine (0.90 mL, 6.42 mmol) in dichloromethane(15 mL) was added phenylacetyl chloride (0.28 mL, 2.14 mmol) dropwise,then the reaction mixture was stirred at room temperature overnight. Thereaction mixture was diluted with dichloromethane, and then washed with2 N HCl. The aqueous layer was extracted with dichloromethane. Thecombined organic layers were washed with brine, dried (Na₂SO₄), filteredand concentrated. The crude product was dissolved in toluene (8 mL) andthe solution was treated with p-toluenesulfonic acid monohydrate (537mg, 2.83 mmol). The reaction mixture was then heated to reflux for 5 h.The reaction was cooled to room temperature, poured into water andextracted with ethyl acetate. The organic layer was separated, thenwashed with water (3×100 mL), brine, dried (Na₂SO₄), filtered andconcentrated to afford 2-benzylbenzoxazole-4-carboxylic acid (277 mg,51%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 13.08 (br s, 1H),7.91 (dd, J=7.1, 1.0 Hz, 1H), 7.85 (dd, J=7.7, 1.0 Hz, 1H), 7.44 (t,J=7.9 Hz, 1H), 7.40-7.34 (m, 4H), 7.31-7.27 (m, 1H), 4.40 (s, 2H); MS(ESI+) m/z 254 (M+H).

Step B: A mixture of 2-benzylbenzoxazole-4-carboxylic acid (76 mg, 0.30mmol), endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride(86 mg, 0.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (115 mg, 0.60 mmol) and 1-hydroxybenzotriazole (81 mg,0.60 mmol) in DMF (3 mL) was stirred at room temperature for 5 min, thentriethylamine (0.17 mL, 1.28 mmol) was added. The resulting reactionmixture was stirred at room temperature for 12 h. The mixture wasdiluted with ethyl acetate (20 mL), and then washed with a saturatedsolution of sodium bicarbonate (10 mL). The aqueous layer was furtherextracted with ethyl acetate (3×25 mL). The combined organics were dried(Na₂SO₄), filtered and concentrated. The crude material was purified bycolumn chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford thecarboxamide (81 mg, 70%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ8.93 (br s, 1H), 8.14 (dd, J=8.0, 1.0 Hz, 1H), 7.59 (dd, J=8.0, 1.0 Hz,1H), 7.42-7.27 (m, 6H), 4.60-4.50 (m, 1H), 4.32 (s, 2H), 3.20-3.10 (m,2H), 2.65-2.50 (m, 2H), 2.58 (s, 3H), 2.15-1.95 (m, 3H), 1.60-1.50 (m,3H), 1.22-1.10 (m, 2H); MS (ESI+) m/z 390 (M+H).

Step C: To a solution ofendo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-benzylbenzoxazole-4-carboxamide(78 mg, 0.2 mmol) in methanol (1.5 mL) was added a solution of HCl indiethyl ether (1 N, 0.4 mL, 0.4 mmol) at room temperature slowly. Thereaction mixture was diluted with diethyl ether. The resulting solid wasfiltered and washed with diethyl ether to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-benzylbenzoxazole-4-carboxamidehydrochloride (89 mg, quantitative) as a white solid: ¹H NMR (500 MHz,DMSO-d₆) δ 10.62 (br s, 0.3H), 10.27 (br s, 0.7H), 9.12 (d, J=7.3 Hz,0.3H), 8.90 (d, J=7.3 Hz, 0.7H), 7.95-7.85 (m, 2H), 7.55-7.48 (m, 1H),7.45-7.38 (m, 4H), 7.35-7.30 (m, 1H), 4.60-4.55 (m, 0.7H), 4.47 (s,1.3H), 4.46 (s, 0.7H), 4.31-4.28 (m, 0.3H), 3.64-3.56 (m, 1.3H),3.52-3.45 (m, 0.7H), 2.84-2.80 (m, 3H), 2.75-2.60 (m, 2H), 2.30-2.20 (m,3H), 1.80-1.30 (m, 5H); MS (ESI+) m/z 390 (M+H); HPLC 97.6% (AUC),t_(R)=12.10 min.

Example 10 Preparation of(S)—N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-benzylbenzoxazole-4-carboxamideHydrochloride

Step A: A mixture of 2-benzylbenzoxazole-4-carboxylic acid (76 mg, 0.30mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (75 mg, 0.38 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg,0.60 mmol) and 1-hydroxybenzotriazole (81 mg, 0.60 mmol) in DMF (3 mL)was stirred at room temperature for 5 min, then triethylamine (0.13 mL,0.90 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 12 h. The mixture was diluted with ethyl acetate (50mL), then washed with a saturated solution of sodium bicarbonate. Theaqueous layer was further extracted with ethyl acetate (3×25 mL). Thecombined organics were dried (Na₂SO₄), filtered and concentrated. Thecrude material was purified by column chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford thecarboxamide (89 mg, 82%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ9.34 (d, J=7.1 Hz, 1H), 8.12 (dd, J=8.0, 1.0 Hz, 1H), 7.63 (dd, J=8.0,1.0 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.40-7.32 (m, 5H), 4.32 (s, 2H),4.31-4.26 (m, 1H), 3.50-3.43 (m, 1H), 3.00-2.82 (m, 2H), 2.75-2.68 (m,1H), 2.10-2.05 (m, 1H), 1.81-1.70 (m, 3H), 1.55-1.45 (m, 3H); MS (ESI+)m/z 362 (M+H).

Step B: To a solution of(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzylbenzoxazole-4-carboxamide(84 mg, 0.23 mmol) in methanol (1.5 mL) was added a solution of HCl indiethyl ether (1 N, 0.5 mL, 0.5 mmol) at room temperature slowly. Thereaction mixture was diluted with diethyl ether. The resulting solid wasfiltered and washed with diethyl ether to afford(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzylbenzoxazole-4-carboxamidehydrochloride (71 mg, 78%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ10.05 (br s, 1H), 9.19 (d, J=7.1 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.88(d, J=8.0 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.45-7.30 (m, 5H), 4.48 (s,2H), 4.37-4.32 (m, 1H), 3.75-3.65 (m, 1H), 3.22-3.15 (m, 3H), 3.10-3.05(m, 2H), 2.15-2.10 (m, 1H), 1.95-1.90 (m, 2H), 1.80-1.60 (m, 2H); MS(ESI+) m/z 362 (M+H); HPLC >99% (AUC), t_(R)=11.81 min.

Example 11 Preparation ofEndo-N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(cyclopropylmethyl)benzoxazole-4-carboxamideHydrochloride

Step A: To an ice-cold solution of 2-cyclopropyl acetic acid (321 mg,3.21 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.29mL, 3.21 mmol) dropwise and a few drops of DMF. The ice bath was removedand stirring was continued for 1 h. 2-Amino-3-hydroxybenzoic acidhydrobromide (750 mg, 3.21 mmol) was added followed by triethylamine(0.90 mL, 6.42 mmol). The resulting reaction mixture was stirred at roomtemperature overnight. The reaction was quenched with aqueous 1 N HCl(25 mL) until the solution reached pH 1. The reaction mixture wasextracted with dichloromethane. The combined organic layers were driedover Na₂SO₄, filtered and concentrated to a brown solid. The crude wasdissolved in toluene (10 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (735 mg, 3.87 mmol). The reactionmixture was then heated to reflux for 3 h. The reaction was cooled toroom temperature, poured into water and extracted with ethyl acetate.The organic layer was separated, washed with water (5×50 mL) and brine,dried (Na₂SO₄), filtered, and concentrated. The crude was purified byrecrystallization from diethyl ether and hexanes to afford2-(cyclopropylmethyl)benzoxazole-4-carboxylic acid (441 mg, 63%) as alight brown solid: ¹H NMR (500 MHz, DMSO-d₆) δ 13.04 (br s, 1H), 7.94(dd, J=8.1, 0.9 Hz, 1H), 7.81 (dd, J=7.8, 0.9 Hz, 1H), 7.45 (t, J=7.9Hz, 1H), 2.92 (d, J=7.0 Hz, 2H), 1.27-1.16 (m, 1H), 0.60-0.54 (m, 2H),0.36-0.30 (m, 2H); MS (ESI+) m/z 218 (M+H).

Step B: A mixture of 2-(cyclopropylmethyl)benzoxazole-4-carboxylic acid(100 mg, 0.46 mmol), endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (129 mg, 0.57 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (175 mg,0.92 mmol) and 1-hydroxybenzotriazole (124 mg, 0.92 mmol) in DMF (2 mL)was stirred at room temperature for 5 min, then triethylamine (0.19 mL,1.28 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 12 h. The mixture was diluted with ethyl acetate (20mL), then washed with a saturated solution of sodium bicarbonate (15mL). The aqueous layer was further extracted with ethyl acetate (3×100mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:9:1 dichloromethane/methanol/concentrated ammoniumhydroxide) to afford the carboxamide (101 mg, 62%) as a light brownsemi-solid: ¹H NMR (500 MHz, CDCl₃) δ 9.03 (d, J=6.4 Hz, 1H), 8.15 (dd,J=7.8, 1.0 Hz, 1H), 7.61 (dd, J=8.0, 0.9 Hz, 1H), 7.41 (t, J=7.9 Hz,1H), 4.50-4.40 (m, 1H), 3.20-3.10 (m, 2H), 2.90 (d, J=7.0 Hz, 2H),2.63-2.58 (m, 2H), 2.56 (s, 3H), 2.15-1.95 (m, 3H), 1.60-1.50 (m, 3H),1.30-1.22 (m, 1H), 1.20-1.10 (m, 2H), 0.71-0.60 (m, 2H), 0.42-0.34 (m,2H); MS (ESI+) m/z 354 (M+H).

Step C: To a solution ofendo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1-methylcyclopropyl)benzoxazole-4-carboxamide(98 mg, 0.27 mmol) in methanol (0.5 mL) was added a solution of HCl indiethyl ether (1 N, 0.35 mL, 0.35 mmol) at room temperature slowly. Thereaction mixture was diluted with diethyl ether. The resulting solid wasfiltered and washed with diethyl ether to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(cyclopropylmethyl)benzoxazole-4-carboxamidehydrochloride (55 mg, 52%) as a light brown solid: ¹H NMR (500 MHz,DMSO-d₆) δ 10.30 (br s, 0.3H), 9.60 (br s, 0.7H), 9.26 (d, J=7.3 Hz,0.3H), 8.97 (d, J=7.3 Hz, 0.7H), 7.95-7.88 (m, 2H), 7.55-7.48 (m, 1H),4.65-4.58 (m, 0.7H), 4.38-4.30 (m, 0.3H), 3.70-3.66 (m, 1.3H), 3.62-3.58(m, 0.7H), 2.94 (s, 2H), 2.88-2.82 (m, 3H), 2.75-2.60 (m, 2H), 2.28-2.20(m, 1H), 2.18-2.05 (m, 2H), 1.82-1.75 (m, 3H), 1.60-1.48 (m, 2H),1.30-1.20 (m, 1H), 0.65-0.55 (m, 2H), 0.40-0.30 (m, 2H); MS (ESI+) m/z354 (M+H); HPLC >99% (AUC), t_(R)=12.22 min.

Example 12 Preparation of(S)—N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(cyclopropylmethyl)benzoxazole-4-carboxamideHydrochloride

Step A: A mixture of 2-(cyclopropylmethyl)benzoxazole-4-carboxylic acid(100 mg, 0.46 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (113mg, 0.57 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (175 mg, 0.92 mmol) and 1-hydroxybenzotriazole (124 mg,0.92 mmol) in DMF (2 mL) was stirred at room temperature for 5 min, thentriethylamine (0.19 mL, 1.38 mmol) was added. The resulting reactionmixture was stirred at room temperature for 12 h. The mixture wasdiluted with ethyl acetate (20 mL), then washed with a saturatedsolution of sodium bicarbonate (10 mL). The aqueous layer was furtherextracted with ethyl acetate (3×15 mL). The combined organics were dried(Na₂SO₄), filtered and concentrated. The crude material was purified bycolumn chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford thecarboxamide (98 mg, 66%) as a light brown semi-solid: ¹H NMR (500 MHz,CDCl₃) δ 9.53 (d, J=7.1 Hz, 1H), 8.14 (dd, J=7.8, 1.0 Hz, 1H), 7.63 (dd,J=8.0, 0.9 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 4.35-4.27 (m, 1H), 3.54-3.46(m, 1H), 3.10-2.90 (m, 6H), 2.78 (dd, J=14.0, 4.5 Hz, 1H), 2.15-2.10 (m,1H), 2.08-2.01 (m, 1H), 1.82-1.75 (m, 2H), 1.64-1.57 (m, 1H), 1.35-1.25(m, 1H), 0.71-0.60 (m, 2H), 0.42-0.34 (m, 2H); MS (ESI+) m/z 326 (M+H).

Step B: To a solution of(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(cyclopropylmethyl)benzoxazole-4-carboxamide(94 mg, 0.29 mmol) in methanol (0.5 mL) was added a solution of HCl indiethyl ether (1 N, 0.32 mL, 0.34 mmol) at 0° C. slowly. The reactionmixture was diluted with diethyl ether. The resulting solid was filteredand washed with diethyl ether to afford(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(cyclopropylmethyl)benzoxazole-4-carboxamidehydrochloride (81 mg, 77%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ10.12 (br s, 1H), 9.36 (d, J=6.6 Hz, 1H), 7.97 (d, J=8.1 Hz, 2H), 7.46(t, J=7.9 Hz, 1H), 4.45-4.38 (m, 1H), 3.80-3.47 (m, 1H), 3.28-3.22 (m,2H), 3.15 (dd, J=14.0, 4.5 Hz, 1H), 3.00 (d, J=7.0 Hz, 2H), 2.30-2.16(m, 2H), 2.00-1.90 (m, 3H), 1.61 (s, 3H), 1.48-1.40 (m, 2H), 1.20-1.15(m, 2H); MS (ESI+) m/z 326 (M+H); HPLC >99% (AUC), t_(R)=11.65 min.

Example 13 Preparation ofEndo-N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-methylcyclopropyl)benzoxazole-4-carboxamideHydrochloride

Step A: To an ice-cold solution of 2-methylcyclopropanecarboxylic acid(214 mg, 2.14 mmol) in dichloromethane (10 mL) was added oxalyl chloride(0.19 mL, 2.14 mmol) dropwise and a few drops of DMF. The ice bath wasremoved and stirring was continued for 1 h. 2-Amino-3-hydroxybenzoicacid hydrobromide (500 mg, 2.14 mmol) was added followed bytriethylamine (0.90 mL, 6.42 mmol). The resulting reaction mixture wasstirred at room temperature overnight. The reaction was quenched withaqueous 1 N HCl (25 mL) until the solution reached pH 1. The reactionmixture was extracted with dichloromethane. The combined organic layerswere dried over Na₂SO₄, filtered and concentrated to a brown solid. Thecrude was dissolved in toluene (10 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (574 mg, 3.0 mmol). The reactionmixture was then heated to reflux for 5 h. The reaction was cooled toroom temperature, poured into water and extracted with ethyl acetate.The organic layer was separated then washed with water (5×150 mL),brine, dried (Na₂SO₄), filtered and concentrated to afford2-(2-methylcyclopropyl)benzoxazole-4-carboxylic acid (409 mg, 88%) as ayellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 12.92 (br s, 1H), 7.84 (dd,J=8.1, 1.0 Hz, 1H), 7.81 (dd, J=7.8, 1.0 Hz, 1H), 7.38 (t, J=7.9 Hz,1H), 2.10-2.05 (m, 1H), 1.62-1.57 (m, 1H), 1.41-1.34 (m, 1H), 1.28 (d,J=6.5 Hz, 3H), 1.08-1.02 (m, 1H); MS (ESI+) m/z 218 (M+H).

Step B: A mixture of 2-(2-methylcyclopropyl)benzoxazole-4-carboxylicacid (200 mg, 0.92 mmol),endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (261 mg,1.15 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(351 mg, 1.84 mmol) and 1-hydroxybenzotriazole (248 mg, 1.15 mmol) inDMF (2 mL) was stirred at room temperature for 5 min, then triethylamine(0.38 mL, 2.76 mmol) was added. The resulting reaction mixture wasstirred at room temperature for 12 h. The mixture was diluted withdichloromethane (100 mL), then washed with a saturated solution ofsodium bicarbonate (20 mL). The aqueous layer was further extracted withdichloromethane (3×150 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 dichloromethane/methanol/concentratedammonium hydroxide) to afford the carboxamide (207 mg, 64%) as a brownsolid: ¹H NMR (500 MHz, CDCl₃) δ 8.95 (d, J=6.4 Hz, 1H), 8.11 (dd,J=7.8, 1.0 Hz, 1H), 7.51 (dd, J=8.0, 0.9 Hz, 1H), 7.32 (t, J=7.9 Hz,1H), 4.50-4.40 (m, 1H), 3.20-3.10 (m, 2H), 2.65-2.57 (m, 2H), 2.56 (s,3H), 2.15-1.95 (m, 4H), 1.75-1.65 (m, 1H), 1.60-1.40 (m, 4H), 1.30-1.24(m, 3H), 1.20-1.15 (m, 2H), 1.09-1.05 (m, 1H); MS (ESI+) m/z 354 (M+H).

Step C: To a solution ofendo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(2-methylcyclopropyl)benzoxazole-4-carboxamide(201 mg, 0.57 mmol) in methanol (0.5 mL) was added a solution of HCl indiethyl ether (1 N, 1.13 mL, 1.13 mmol) at room temperature slowly. Thereaction mixture was diluted with diethyl ether. The resulting solid wasfiltered and washed with diethyl ether to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-methylcyclopropyl)benzoxazole-4-carboxamidehydrochloride (221 mg, 98%) as a white solid and as a mixture ofdiastereomers: ¹H NMR (500 MHz, CDCl₃) δ 12.24 (br s, 0.4H), 11.79 (brs, 0.6H), 9.41 (d, J=5.9 Hz, 0.4H), 9.35 (d, J=5.6 Hz, 0.6H), 8.08 (dd,J=7.8, 0.9 Hz, 0.4H), 8.04 (dd, J=7.8, 0.9 Hz, 0.6H), 7.59 (dd, J=8.1,0.9 Hz, 0.4H), 7.54 (dd, J=8.1, 0.9 Hz, 0.6H), 7.38 (t, J=7.9 Hz, 0.4H),7.34 (t, J=7.9 Hz, 0.6H), 4.76-4.70 (m, 0.7H), 4.56-4.52 (m, 0.3H),3.65-3.60 (m, 2H), 2.95-2.55 (m, 7H), 2.15-2.05 (m, 1H), 2.02-1.90 (m,2H), 1.85-1.60 (m, 5H), 1.52-1.42 (m, 1H), 1.32-1.28 (m, 3H), 1.15-1.05(m, 1H); MS (ESI+) m/z 354 (M+H); HPLC >99% (AUC), t_(R)=12.01 min.

Example 14 Preparation of(S)—N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2-methylcyclopropyl)benzoxazole-4-carboxamideHydrochloride

Step A: A mixture of 2-(2-methylcyclopropyl)benzoxazole-4-carboxylicacid (200 mg, 0.92 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride(229 mg, 1.15 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (351 mg, 1.84 mmol) and 1-hydroxybenzotriazole (248 mg,1.84 mmol) in DMF (6 mL) was stirred at room temperature for 5 min, thentriethylamine (0.38 mL, 2.76 mmol) was added. The resulting reactionmixture was stirred at room temperature for 12 h. The mixture wasdiluted with dichloromethane (100 mL), then washed with a saturatedsolution of sodium bicarbonate (20 mL). The aqueous layer was furtherextracted with dichloromethane (3×150 mL). The combined organics weredried (Na₂SO₄), filtered and concentrated. The crude material waspurified by column chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford theproduct (155 mg, 52%) as a colorless semi-solid and as a mixture of twodiastereomers: ¹H NMR (500 MHz, CDCl₃) δ 9.44 (d, J=7.1 Hz, 1H), 8.10(dd, J=7.5, 1.0 Hz, 1H), 7.56 (dd, J=8.0, 2.0 Hz, 1H), 7.34 (t, J=8.0Hz, 1H), 4.32-4.26 (m, 1H), 3.54-3.46 (m, 1H), 3.10-2.90 (m, 4H), 2.75(dd, J=14.0, 4.5 Hz, 1H), 2.15-2.10 (m, 1H), 2.04-1.94 (m, 2H),1.80-1.75 (m, 2H), 1.70-1.60 (m, 2H), 1.50-1.45 (m, 1H), 1.28 (d, J=6.5Hz, 3H), 1.10-1.05 (m, 1H); MS (ESI+) m/z 326 (M+H).

Step B: To a solution of(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2-methylcyclopropyl)benzoxazole-4-carboxamide(149 mg, 0.45 mmol) in methanol (0.5 mL) was added a solution of HCl indiethyl ether (1 N, 0.92 mL, 0.92 mmol) at room temperature slowly. Thereaction mixture was diluted with diethyl ether. The resulting solid wasfiltered and washed with diethyl ether to afford(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2-methylcyclopropyl)benzoxazole-4-carboxamidehydrochloride (82 mg, 51%) as a white solid and as a mixture ofdiastereomers: ¹H NMR (500 MHz, DMSO-d₆) δ 12.68 (br s, 1H), 9.51 (br s,1H), 8.12 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.38 (t, J=7.9 Hz,1H), 4.69-4.58 (m, 1H), 3.80-3.70 (m, 1H), 3.50-3.20 (m, 5H), 2.60-2.50(m, 1H), 2.40-2.35 (m, 1H), 2.25-1.95 (m, 4H), 1.65-1.60 (m, 1H),1.50-1.42 (m, 1H), 1.35-1.30 (m, 2H), 1.17-1.10 (m, 2H); MS (ESI+) m/z326 (M+H); HPLC 98.9% (AUC), t_(R)=11.59 min.

Example 15 Preparation ofEndo-N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-cyclohexylbenzoxazole-4-carboxamideHydrochloride

Step A: To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (500mg, 2.13 mmol) and cyclohexane carbonyl chloride (0.29 mL, 2.13 mmol) indichloromethane (20 mL) was added triethylamine (0.90 mL, 6.41 mmol)dropwise, then the reaction mixture was stirred at room temperature for12 h. The reaction mixture was diluted with dichloromethane, and thenwashed with 2 N HCl. The aqueous layer was extracted withdichloromethane. The combined organic layers were washed with brine,dried (Na₂SO₄), filtered and concentrated. The crude product wasdissolved in toluene (8 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (485 mg, 2.55 mmol). The reactionmixture was then heated to reflux for 5 h. The reaction was cooled toroom temperature, poured into water and extracted with ethyl acetate.The organic layer was separated, then washed with water (7×100 mL),brine, dried (Na₂SO₄), filtered and concentrated. The crude product waspurified by re-crystallization from ethyl acetate and hexanes to afford2-cyclohexylbenzoxazole-4-carboxylic acid (346 mg, 66%) as a brownsolid: ¹H NMR (500 MHz, DMSO-d₆) δ 13.01 (br s, 1H), 7.92 (dd, J=8.0,0.9 Hz, 1H), 7.84 (dd, J=7.8, 0.9 Hz 1H), 7.44 (t, J=7.8 Hz, 1H),3.08-3.02 (m, 1H), 2.14-2.05 (m, 2H), 1.82-1.75 (m, 2H), 1.72-1.60 (m,3H), 1.47-1.38 (m, 2H), 1.35-1.25 (m, 1H); MS (ESI+) m/z 246 (M+H).

Step B: A mixture of 2-cyclohexylbenzoxazole-4-carboxylic acid (100 mg,0.41 mmol), endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (118 mg, 0.51 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (175 mg,0.82 mmol) and 1-hydroxybenzotriazole (109 mg, 0.82 mmol) in DMF (5 mL)was stirred at room temperature for 5 min, then triethylamine (0.17 mL,1.26 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 12 h. The mixture was diluted with dichloromethane (20mL), then washed with a saturated solution of sodium bicarbonate (10mL). The aqueous layer was further extracted with dichloromethane (3×50mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:9:1 dichloromethane/methanol/concentrated ammoniumhydroxide) to afford the carboxamide (143 mg, 91%) as a light brownsemi-solid: ¹H NMR (500 MHz, CDCl₃) δ 9.11 (d, J=6.0 Hz, 1H), 8.13 (dd,J=8.0, 1.0 Hz, 1H), 7.59 (dd, J=8.0, 0.9 Hz, 1H), 7.39 (t, J=8.0 Hz,1H), 4.62-4.52 (m, 1H), 3.05-3.00 (m, 1H), 2.61-2.55 (m, 2H), 2.60 (s,3H), 2.21-2.00 (m, 5H), 1.90-1.86 (m, 2H), 1.78-1.70 (m, 4H), 1.65-1.35(m, 9H); MS (ESI+) m/z 382 (M+H).

Step C: To a solution of the carboxamide of step B (136 mg, 0.35 mmol)in methanol (1.0 mL) was added a solution of HCl in diethyl ether (1 N,0.71 mL, 0.71 mmol) at 0° C. slowly. The reaction mixture was dilutedwith diethyl ether. The resulting solid was filtered and washed withdiethyl ether to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-cyclohexylbenzoxazole-4-carboxamidehydrochloride (159 mg, quantitative) as a white solid: ¹H NMR (500 MHz,CDCl₃) δ 12.24 (br s, 0.3H), 11.83 (br s, 0.7H), 9.53 (d, J=5.4 Hz,0.3H), 9.39 (d, J=5.4 Hz, 0.7H), 8.12 (dd, J=7.7, 0.8 Hz, 0.3H), 8.08(dd, J=7.7, 0.8 Hz, 0.7H), 7.66 (dd, J=8.1, 0.8 Hz, 0.3H), 7.62 (dd,J=8.1, 0.8 Hz, 0.7H), 7.44 (t, J=7.9 Hz, 0.3H), 7.40 (t, J=7.9 Hz,0.7H), 4.75-4.68 (m, 0.7H), 4.56-4.50 (m, 0.3H), 3.65-3.50 (m, 2H),3.05-3.00 (m, 1H), 2.95-2.82 (m, 5H), 2.80-2.60 (m, 2H), 2.20-2.05 (m,4H), 2.00-1.65 (m, 9H), 1.50-1.25 (m, 3H); MS (ESI+) m/z 382 (M+H);HPLC >99% (AUC), t_(R)=12.72 min.

Example 16 Preparation of(S)—N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-cyclohexylbenzoxazole-4-carboxamideHydrochloride

Step A: A mixture of 2-cyclohexylbenzoxazole-4-carboxylic acid (100 mg,0.41 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (102 mg, 0.51mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (155mg, 0.81 mmol) and 1-hydroxybenzotriazole (109 mg, 0.81 mmol) in DMF (5mL) was stirred at room temperature for 5 min, then triethylamine (0.17mL, 1.28 mmol) was added. The resulting reaction mixture was stirred atroom temperature for 12 h. The mixture was diluted with ethyl acetate(20 mL), then washed with a saturated solution of sodium bicarbonate (20mL). The aqueous layer was further extracted with ethyl acetate (3×100mL). The combined organics were washed with water (3×150 mL), dried(Na₂SO₄), filtered and concentrated. The crude material was purified bycolumn chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford thecarboxamide (139 mg, 95%) as a light brown solid: ¹H NMR (500 MHz,CDCl₃) δ 9.58 (d, J=6.5 Hz, 1H), 8.12 (dd, J=7.8, 1.0 Hz, 1H), 7.61 (dd,J=8.0, 0.9 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 4.35-4.28 (m, 1H), 3.55-3.45(m, 1H), 3.10-2.90 (m, 5H), 2.81 (dd, J=14.0, 4.5 Hz, 1H), 2.24-2.22 (m,2H), 2.16-2.11 (m, 1H), 2.10-2.00 (m, 1H), 1.90-1.85 (m, 2H), 1.80-1.68(m, 5H), 1.66-1.57 (m, 1H), 1.53-1.42 (m, 2H), 1.40-1.34 (m, 1H); MS(ESI+) m/z 354 (M+H).

Step B: To a solution of(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclohexylbenzoxazole-4-carboxamide(136 mg, 0.39 mmol) in methanol (1.0 mL) was added a solution of HCl indiethyl ether (1 N, 0.8 mL, 0.8 mmol) at room temperature slowly. Thereaction mixture was diluted with diethyl ether. The resulting solid wasfiltered and washed with diethyl ether to afford(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclohexylbenzoxazole-4-carboxamidehydrochloride (147 mg, 96%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ12.68 (br s, 1H), 9.62 (d, J=6.5 Hz, 1H), 8.11 (dd, J=7.8, 1.0 Hz, 1H),7.67 (dd, J=8.0, 0.9 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 4.70-4.63 (m, 1H),3.80-3.74 (m, 1H), 3.45-3.28 (m, 3H), 3.25-3.15 (m, 1H), 3.07-3.00 (m,1H), 2.53-2.46 (m, 1H), 2.40-2.30 (m, 1H), 2.24-2.07 (m, 4H), 2.05-1.95(m, 1H), 1.93-1.84 (m, 2H), 1.83-1.63 (m, 4H), 1.55-1.42 (m, 2H),1.40-1.30 (m, 1H); MS (ESI+) m/z 354 (M+H); HPLC >99% (AUC), t_(R)=12.30min.

Example 17 Preparation ofEndo-N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-cyclobutylbenzoxazole-4-carboxamideHydrochloride

Step A: To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (0.50g, 2.13 mmol) and cyclobutanecarbonyl chloride (0.24 mL, 2.13 mmol) indichloromethane (20 mL) was added triethylamine (0.90 mL, 6.41 mmol)dropwise, then the reaction mixture was stirred at room temperature for12 h. The reaction mixture was diluted with dichloromethane, and thenwashed with 2 N HCl. The aqueous layer was extracted withdichloromethane. The combined organic layers were washed with brine,dried (Na₂SO₄), filtered and concentrated. The crude product wasdissolved in toluene (8 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (676 mg, 3.56 mmol). The reactionmixture was then heated to reflux for 5 h. The reaction was cooled toroom temperature, poured into water and extracted with ethyl acetate.The combined organic layers were washed with water and brine, dried(Na₂SO₄), filtered and concentrated. The crude product was purified byre-crystallization from ethyl acetate and hexanes to afford2-cyclobutylbenzoxazole-4-carboxylic acid (420 mg, 73%) as a brownsolid: ¹H NMR (500 MHz, DMSO-d₆) δ 12.96 (br s, 1H), 7.92 (dd, J=8.1,0.8 Hz, 1H), 7.84 (dd, J=7.6, 0.8 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H),3.95-3.85 (m, 1H), 2.46-2.39 (m, 4H), 2.28-2.00 (m, 2H); MS (ESI+) m/z218 (M+H).

Step B: A mixture of 2-cyclobutylbenzoxazole-4-carboxylic acid (208 mg,0.96 mmol), endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (238 mg, 0.19 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (367 mg,1.92 mmol) and 1-hydroxybenzotriazole (259 mg, 1.92 mmol) in DMF (10 mL)was stirred at room temperature for 5 min, then triethylamine (0.54 mL,3.84 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 12 h. The mixture was diluted with dichloromethane (100mL), then washed with a saturated solution of sodium bicarbonate (50mL). The aqueous layer was further extracted with dichloromethane (3×150mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:9:1 dichloromethane/methanol/concentrated ammoniumhydroxide) to afford the amide (241 mg, 71%) as a light brownsemi-solid: ¹H NMR (300 MHz, CDCl₃) δ 9.11 (d, J=6.0 Hz, 1H), 8.14 (dd,J=8.0, 1.0 Hz, 1H), 7.59 (dd, J=8.0, 0.9 Hz, 1H), 7.40 (t, J=8.0 Hz,1H), 4.60-4.50 (m, 1H), 3.90-3.80 (m, 1H), 3.30-3.20 (m, 2H), 2.61-2.55(m, 6H), 2.60 (s, 3H), 2.30-2.00 (m, 6H), 1.60-1.50 (m, 2H), 1.20-1.10(m, 2H); MS (ESI+) m/z 354 (M+H).

Step C: To a solution of the carboxamide from step B (239 mg, 0.67 mmol)in methanol (1.0 mL) was added a solution of HCl in diethyl ether (1 N,1.35 mL, 1.35 mmol) at room temperature slowly. The reaction mixture wasdiluted with diethyl ether. The resulting solid was filtered and washedwith diethyl ether to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-cyclobutylbenzoxazole-4-carboxamidehydrochloride (15 mg, 6%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ12.26 (br s, 0.4H), 11.84 (br s, 0.6H), 9.53 (d, J=5.6 Hz, 0.4H), 9.39(d, J=5.6 Hz, 0.6H), 8.13 (dd, J=7.7, 0.8 Hz, 0 4H), 8.09 (dd, J=7.7,0.8 Hz, 0.6H), 7.66 (dd, J=8.1, 0.8 Hz, 0.4H), 7.62 (dd, J=8.1, 0.8 Hz,0.6H), 7.47 (t, J=7.9 Hz, 0.4H), 7.41 (t, J=7.9 Hz, 0.6H), 4.78-4.70 (m,0.6H), 4.56-4.50 (m, 0.4H), 3.39-3.38 (m, 1H), 3.60-3.55 (m, 2H),2.95-2.82 (m, 5H), 2.80-2.45 (m, 6H), 2.30-2.22 (m, 3H), 2.00-1.90 (m,1H), 1.85-1.60 (m, 4H); MS (ESI+) m/z 354 (M+H); HPLC >99% (AUC),t_(R)=12.72 min.

Example 18 Preparation of(S)—N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-cyclobutylbenzoxazole-4-carboxamideHydrochloride

Step A: A mixture of 2-cyclobutylbenzoxazole-4-carboxylic acid (208 mg,0.96 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (238 mg, 1.19mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (367mg, 1.92 mmol) and 1-hydroxybenzotriazole (259 mg, 1.92 mmol) in DMF (10mL) was stirred at room temperature for 5 min, then triethylamine (0.54mL, 3.84 mmol) was added. The resulting reaction mixture was stirred atroom temperature for 12 h. The mixture was diluted with dichloromethane(100 mL), then washed with a saturated solution of sodium bicarbonate(50 mL). The aqueous layer was further extracted with dichloromethane(3×150 mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 89:10:1 dichloromethane/methanol/concentrated ammoniumhydroxide) to afford the amide (229 mg, 73%) as a light brown solid: ¹HNMR (500 MHz, CDCl₃) δ 9.57 (d, J=7.8 Hz, 1H), 8.13 (dd, J=7.8, 1.0 Hz,1H), 7.62 (dd, J=8.0, 0.9 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 4.36-4.26 (m,1H), 3.90-3.76 (m, 1H), 3.56-3.46 (m, 1H), 3.10-2.90 (m, 4H), 2.82 (dd,J=14.0, 4.5 Hz, 1H), 2.60-2.48 (m, 4H), 2.30-2.00 (m, 4H), 1.84-1.72 (m,2H), 1.60-1.55 (m, 1H); MS (ESI+) m/z 326 (M+H).

Step B: To a solution of(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclobutylbenzoxazole-4-carboxamide(226 mg, 0.69 mmol) in methanol (1.0 mL) was added a solution of HCl indiethyl ether (1 N, 0.8 mL, 0.8 mmol) at room temperature slowly. Thereaction mixture was diluted with diethyl ether. The resulting solid wasfiltered and washed with diethyl ether to afford(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclobutylbenzoxazole-4-carboxamidehydrochloride (151 mg, 60%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ12.68 (br s, 1H), 9.61 (d, J=7.0 Hz, 1H), 8.13 (dd, J=7.8, 1.0 Hz, 1H),7.62 (dd, J=8.0, 0.9 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 4.68-4.62 (m, 1H),3.90-3.75 (m, 2H), 3.50-3.23 (m, 5H), 2.60-2.50 (m, 5H), 2.40-2.30 (m,1H), 2.25-1.95 (m, 5H); MS (ESI+) m/z 326 (M+H); HPLC >99% (AUC),t_(R)=11.60 min.

Example 19 Preparation of(S)—N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-fluoro-2-cyclopropylbenzoxazole-4-carboxamideHydrochloride

Step A: Iodine (3.6 g, 14.2 mmol) was added to a mixture of methyl2-amino-5-fluorobenzoate (2.4 g, 14.2 mmol), silver sulfate (4.42 g,14.2 mmol) and ethanol (30 mL) at room temperature. The mixture wasstirred under nitrogen for 1 h, and then quenched with a saturatedsolution of sodium bicarbonate, extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried (Na₂SO₄), filteredand concentrated. The crude material was purified by columnchromatography (silica gel, 90:10 hexanes/ethyl acetate) to affordmethyl 2-amino-5-fluoro-3-iodobenzoate (3.9 g, 93%) as a light yellowsolid: ¹H NMR (300 MHz, CDCl₃) δ 7.66-7.58 (m, 2H), 6.21 (br s, 2H),3.89 (s, 3H); ¹⁹F NMR (282 MHz, CDCl₃) δ 127.87; MS (ESI+) m/z 296(M+H).

Step B: A mixture of methyl 2-amino-5-fluoro-3-iodobenzoate from Step A(500 mg, 1.69 mmol), bis(pinacolato)diboron (515 mg, 2.03 mmol),potassium acetate (497 mg, 5.07 mmol), and toluene (10 mL) wasdeoxygenated with nitrogen for 15 min. PdCl₂(dppf) (277 mg, 0.34 mmol)was added. The mixture was heated at 100° C. under nitrogen for 24 h andthen cooled to room temperature, quenched with a saturated solution ofsodium bicarbonate, extracted with ethyl acetate. The combined organiclayers were washed with brine, dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:10 hexanes/ethyl acetate) to afford the borolane (264mg, 53%) as a light yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 7.64 (dd,J=9.6, 3.3 Hz, 1H), 7.52 (dd, J=8.1, 3.3 Hz, 1H), 6.88 (br s, 2H), 3.85(s, 3H), 1.35 (s, 12H); ¹⁹F NMR (282 MHz, CDCl₃) δ 131.16; MS (ESI+) m/z296 (M+H).

Step C: Cyclopropanecarboxylic acid chloride (0.26 mL, 2.9 mmol) wasadded to a solution of the amine from Step B (560 mg, 1.90 mmol) inmethylene chloride (5 mL) at room temperature, followed by triethylamine(0.53 mL, 3.8 mmol). The mixture was stirred under nitrogen overnightand then quenched with a saturated solution of sodium bicarbonate,extracted with methylene chloride. The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered and concentrated to affordthe crude amide (680 mg, 98%) as a light yellow solid: ¹H NMR (300 MHz,CDCl₃) δ 12.30 (br s, 1H), 7.62-7.54 (m, 2H), 3.95 (s, 3H), 1.80-1.70(m, 1H), 1.41 (dd, J=4.2, 3.3 Hz, 2H), 1.28 (s, 12H), 1.15 (dd, J=7.8,3.3 Hz, 2H); ¹⁹F NMR (282 MHz, CDCl₃) δ 115.70; MS (ESI+) m/z 364 (M+H).

Step D: To a solution of sodium hydroxide (112 mg, 2.81 mmol) and sodiumbicarbonate (628 mg, 7.48 mmol) in water (20 mL) at 0° C., was addedoxone (1.73 g, 2.81 mmol), followed by the borolane from Step C (680 mg,1.87 mmol) in acetone (20 mL). The mixture was allowed to warm to roomtemperature and stirred for 2 h, and then quenched with water, extractedwith methylene chloride. The combined organic layers were washed withbrine, dried (Na₂SO₄), filtered and concentrated. The crude material waspurified by Combi-flash chromatography (silica gel, 90:10 hexanes/ethylacetate) to afford methyl2-(cyclopropanecarboxamido)-5-fluoro-3-hydroxybenzoate (180 mg, 38%) asa white solid: ¹H NMR (300 MHz, CDCl₃) δ 11.30 (br s, 1H), 10.58 (s,1H), 7.29 (dd, J=8.4, 3.0 Hz, 1H), 6.94 (dd, J=8.4, 3.0 Hz, 1H), 3.95(s, 3H), 1.82-1.74 (m, 1H), 1.19-1.14 (m, 2H), 1.04-0.95 (m, 2H); ¹⁹FNMR (282 MHz, CDCl₃) δ 115.74; MS (ESI+) m/z 254 (M+H).

Step E: A mixture of2-(cyclopropanecarboxamido)-5-fluoro-3-hydroxybenzoate from Step D (180mg, 0.71 mmol), p-toluenesulfonic acid monohydrate (202 mg, 1.07 mmol)and toluene (5 mL) was heated at reflux under nitrogen for 3 h. Thereaction mixture was then cooled to room temperature, diluted with ethylacetate, washed with a saturated solution of sodium bicarbonate andbrine, dried over sodium sulfate, filtered and concentrated. The crudematerial was purified by Combi-flash chromatography (silica gel, 60:40hexanes/ethyl acetate) to afford methyl2-cyclopropyl-6-fluorobenzoxazole-4-carboxylate (115 mg, 69%) as a whitesolid: ¹H NMR (300 MHz, CDCl₃) δ 7.68 (dd, J=10.2, 2.4 Hz, 1H), 7.34(dd, J=7.5, 2.4 Hz, 1H), 4.02 (s, 3H), 2.39-2.29 (m, 1H), 1.35-1.29 (m,2H), 1.26-1.17 (m, 2H); ¹⁹F NMR (282 MHz, CDCl₃) δ 116.29; MS (ESI+) m/z236 (M+H).

Step F: A mixture of the ester from Step E (115 mg, 0.49 mmol), 2 N NaOH(2.0 mL, 4.0 mmol), and methanol (5 mL) was stirred at room temperatureunder nitrogen for 2 h. The reaction mixture was acidified with 1 N HCl,extracted with methylene chloride, washed with brine, dried over sodiumsulfate, filtered and concentrated to afford2-cyclopropyl-6-fluorobenzoxazole-4-carboxylic acid (105 mg, 97%) as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 12.90 (br s, 1H), 7.91 (dd,J=8.1, 2.4 Hz, 1H), 7.58 (dd, J=10.2, 2.4 Hz, 1H), 2.39-2.29 (m, 1H),1.25-1.14 (m, 4H); ¹⁹F NMR (282 MHz, CDCl₃) δ-116.79; MS (ESI+) m/z 222(M+H).

Step G: A mixture of 2-cyclopropyl-6-fluorobenzoxazole-4-carboxylic acidfrom Step F (50 mg, 0.23 mmol), (S)-3-aminoquinuclidine dihydrochloride(55 mg, 0.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (88 mg, 0.46 mmol) and 1-hydroxybenzotriazole (62 mg, 0.46mmol) in DMF (5 mL) was stirred under nitrogen at room temperature for10 min, and then triethylamine (0.19 mL, 1.4 mmol) was added. Theresulting reaction mixture was stirred at room temperature overnight,and then was quenched with a saturated solution of sodium bicarbonate,extracted with methylene chloride. The combined organic layers weredried (Na₂SO₄), filtered and concentrated. The crude material waspurified by Combi-flash chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) to afford the desiredamide (50 mg, 67%) as a light yellow solid: ¹H NMR (300 MHz, CDCl₃) δ9.36 (d, J=7.5 Hz, 1H), 7.84 (dd, J=10.5, 2.4 Hz, 1H), 7.29 (dd, J=7.5,2.4 Hz, 1H), 4.24-4.19 (m, 1H), 3.45 (ddd, J=14.0, 9.5, 2.0 Hz, 1H),3.10-2.65 (m, 5H), 2.28-2.06 (m, 2H), 1.95-1.85 (m, 1H), 1.75-1.52 (m,3H), 1.31-1.25 (m, 4H); ¹⁹F NMR (282 MHz, CDCl₃) δ-115.30; MS (ESI+) m/z330 (M+H).

Step H: Hydrogen chloride in diethyl ether (1.0 M, 0.15 mL, 0.15 mmol)was added dropwise to a solution of the amide from Step G (50 mg, 0.15mmol) in methylene chloride (1 mL) and diethyl ether (5 mL) at 0° C. Themixture was stirred for 5 min, and then diethyl ether (30 mL) was added.The resulting solid was filtered, washed with diethyl ether, and driedunder vacuum overnight to afford(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-6-fluoro-2-cyclopropylbenzoxazole-4-carboxamidehydrochloride (45 mg, 82%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ10.26 (br s, 1H), 9.16 (d, J=6.6 Hz, 1H), 7.94 (dd, J=8.1, 2.4 Hz, 1H),7.60 (dd, J=10.5, 2.4 Hz, 1H), 4.42-4.34 (m, 1H), 3.72 (ddd, J=14.0,9.5, 2.0 Hz, 1H), 3.40-3.15 (m, 5H), 2.55-2.45 (m, 1H), 2.28-2.06 (m,2H), 1.95-1.85 (m, 3H), 1.35-1.22 (m, 4H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ-115.68; MS (ESI+) m/z 330 (M+H); HPLC >99% (AUC), t_(R)=11.40 min.

Example 20 Preparation ofEndo-N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-fluoro-2-cyclopropylbenzoxazole-4-carboxamideHydrochloride

Step A: A mixture of methyl2-cyclopropyl-6-fluorobenzoxazole-4-carboxylate (50 mg, 0.23 mmol),endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (64 mg,0.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(88 mg, 0.46 mmol) and 1-hydroxybenzotriazole (62 mg, 0.46 mmol) in DMF(5 mL) was stirred under nitrogen at room temperature for 10 min, andthen triethylamine (0.19 mL, 1.4 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight, and then was quenchedwith a saturated solution of sodium bicarbonate, extracted withmethylene chloride. The combined organic layers were washed with brine,dried (Na₂SO₄), filtered and concentrated. The crude material waspurified by Combi-flash chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) to afford thecarboxamide (62 mg, 77%) as a light yellow solid: ¹H NMR (300 MHz,CDCl₃) δ 8.83 (d, J=7.5 Hz, 1H), 7.86 (dd, J=10.5, 2.4 Hz, 1H), 7.26(dd, J=7.5, 2.4 Hz, 1H), 4.62-4.45 (m, 1H), 3.13-3.06 (m, 2H), 2.62-2.55(m, 2H), 2.54 (s, 3H), 2.35-1.98 (m, 4H), 1.62-1.46 (m, 2H), 1.31-1.13(m, 6H); ¹⁹F NMR (282 MHz, CDCl₃) δ-115.55; MS (ESI+) m/z 358 (M+H).

Step B: Hydrogen chloride in diethyl ether (1.0 M, 0.2 mL, 0.2 mmol) wasadded dropwise to a solution of the amide from Step A (62 mg, 0.17 mmol)in methanol (1 mL) and diethyl ether (5 mL) at 0° C. The mixture wasstirred for 5 min, and then diethyl ether (30 mL) was added. Theresulting solid was filtered, washed with diethyl ether, and dried undervacuum overnight to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-fluoro-2-cyclopropylbenzoxazole-4-carboxamidehydrochloride (46 mg, 68%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ10.25 (br s, 0.4H), 9.72 (br s, 0.6H), 9.07 (d, J=6.0 Hz, 0.4H), 8.81(d, J=6.9 Hz, 0.6H), 7.98-7.90 (m, 1H), 7.65-7.59 (m, 1H), 4.62-4.30 (m,1H), 3.68-3.55 (m, 2H), 2.84 (s, 1.5H), 2.83 (s, 1.5H), 2.68-2.55 (m,2H), 2.45-2.35 (m, 1H), 2.25-1.75 (m, 4H), 1.60-1.46 (m, 3H), 1.35-1.16(m, 6H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ-115.69; MS (ESI+) m/z 358 (M+H);HPLC >99% (AUC), t_(R)=11.86 min.

Example 21 Preparation ofN-(9-Ethyl-9-azabicyclo[3.3.1]non-3-yl)-2-cyclopropylbenzoxazole-4-carboxamideHydrochloride

Step A: A mixture of endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (500 mg, 2.20 mmol), (Boc)₂O (528 mg, 2.42 mmol),triethylamine (0.92 mL, 6.6 mmol) and methylene chloride (10 mL) wasstirred under nitrogen at room temperature overnight, and then quenchedwith a saturated solution of sodium bicarbonate, extracted withmethylene chloride. The combined organic layers were washed with brine,dried (Na₂SO₄), filtered and concentrated to give crude tert-butyl9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbamate (530 mg, 95%) as a whitesolid: ¹H NMR (500 MHz, CDCl₃) δ 4.26 (br s, 1H), 3.98 (br s, 1H),3.03-3.00 (m, 2H), 2.45 (s, 3H), 2.43-2.36 (m, 2H), 1.95-1.86 (m, 3H),1.48-1.46 (m, 1H), 1.44 (s, 9H), 1.16-0.98 (m, 4H); MS (ESI+) m/z 255(M+H).

Step B: To a solution of the carbamate from Step A (430 mg, 1.69 mmol)in THF (2 mL) at 0° C. was added a solution of sodium hydroxide (2.0 g,50 mmol) in water (20 mL), followed by a solution of KMnO₄ (2.0 g, 12.6mmol) in water (100 mL). The mixture was allowed to warm to roomtemperature and stirred overnight. Additional KMnO₄ (2.0 g, 12.6 mmol)solution was added at room temperature and the mixture was stirred foradditional 1 h. The mixture was extracted with methylene chloride. Thecombined organic layers were washed with brine, dried (Na₂SO₄), filteredand concentrated to afford tert-butyl9-azabicyclo[3.3.1]nonan-3-ylcarbamate (360 mg, 89%) as an off-whitesolid: ¹H NMR (500 MHz, CDCl₃) δ 4.32 (br s, 1H), 3.66 (br s, 1H),3.33-3.00 (m, 2H), 2.25-2.00 (m, 2H), 1.85-1.48 (m, 5H), 1.45 (s, 9H),1.40-1.35 (m, 2H), 1.09-1.02 (m, 2H); MS (ESI+) m/z 241 (M+H).

Step C: Ethyl iodide (50 μL, 0.63 mmol) was added to a solution of theamine from Step B (100 mg, 0.42 mmol) in methylene chloride (2 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for30 h. The mixture was quenched with a saturated solution of sodiumbicarbonate and extracted with methylene chloride. The combined organiclayers were washed with brine, dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammoniumhydroxide) to afford tert-butyl9-ethyl-9-azabicyclo[3.3.1]nonan-3-ylcarbamate (50 mg, 45%) as a whitesolid: ¹H NMR (500 MHz, CDCl₃) δ 4.28 (br s, 1H), 3.99 (br s, 1H),3.13-3.10 (m, 2H), 2.63 (q, J=7.0 Hz, 2H), 2.38-2.30 (m, 2H), 1.90-1.82(m, 3H), 1.48-1.46 (m, 1H), 1.44 (s, 9H), 1.16-0.95 (m, 7H); MS (ESI+)m/z 269 (M+H).

Step D: Trifluoroacetic acid (0.5 mL) was added to a solution oftert-butyl 9-ethyl-9-azabicyclo[3.3.1]nonan-3-ylcarbamate from Step C(50 mg, 0.19 mmol) in methylene chloride (1 mL) at room temperature andthe mixture was stirred under nitrogen for 2 h. The mixture wasconcentrated and the residue was dissolved in methanol (1 mL). HCl indiethyl ether (1.0 M, 2.0 mL, 2.0 mmol) was added dropwise at roomtemperature and the mixture was stirred for 5 min. The mixture wasconcentrated again and dried under vacuum overnight to give9-ethyl-9-azabicyclo[3.3.1]nonan-3-amine dihydrochloride (45 mg, 99%) asa white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.75 (br s, 1H), 8.39 (br s,3H), 4.14 (br s, 1H), 3.73-3.71 (m, 2H), 3.25 (q, J=7.0 Hz, 2H),2.55-2.48 (m, 2H), 2.05-1.95 (m, 3H), 1.80-1.76 (m, 1H), 1.50-1.22 (m,7H); MS (ESI+) m/z 169 (M+H).

Step E: A mixture of 2-cyclopropylbenzoxazole-4-carboxylic acid (38 mg,0.19 mmol), 3-amino-9-ethyl-9-azabicyclo[3.3.1]nonane dihydrochloridefrom Step D (45 mg, 0.19 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (72 mg, 0.38mmol) and 1-hydroxybenzotriazole (51 mg, 0.38 mmol) in DMF (5 mL) wasstirred under nitrogen at room temperature for 5 min, and thentriethylamine (0.16 mL, 1.1 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight, and then was quenchedwith a saturated solution of sodium bicarbonate, extracted withmethylene chloride. The combined organic layers were washed with brine,dried (Na₂SO₄), filtered and concentrated. The crude material waspurified by Combi-flash chromatography (silica gel, 90:9:1 ethylacetate/methanol/concentrated ammonium hydroxide) to afford the amide(35 mg, 53%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.91 (d,J=6.5 Hz, 1H), 8.11 (dd, J=7.5, 1.0 Hz, 1H), 7.53 (dd, J=7.5, 1.0 Hz,1H), 7.34 (t, J=7.5 Hz, 1H), 4.60-4.50 (m, 1H), 3.24-3.20 (m, 2H), 2.73(q, J=7.0 Hz, 2H), 2.60-2.50 (m, 2H), 2.30-1.90 (m, 4H), 1.60-1.13 (m,9H), 1.06 (t, J=7.0 Hz, 3H); MS (ESI+) m/z 354 (M+H).

Step F: Hydrogen chloride in diethyl ether (1.0 M, 0.1 mL, 0.1 mmol) wasadded dropwise to a solution of the amide from Step E (35 mg, 0.1 mmol)in methylene chloride (1 mL) and diethyl ether (2 mL) at 0° C. Themixture was stirred for 5 min, and then diethyl ether (30 mL) was added.The resulting solid was filtered, washed with diethyl ether, and driedunder vacuum overnight to affordN-(9-ethyl-9-azabicyclo[3.3.1]non-3-yl)-2-cyclopropylbenzoxazole-4-carboxamidehydrochloride (28 mg, 72%) as an off-white solid: ¹H NMR (500 MHz,DMSO-d₆) δ 9.81 (br s, 0.4H), 9.13 (d, J=5.5 Hz, 1H), 9.12 (br s, 0.6H),8.88 (d, J=6.5 Hz, 1H), 7.96-7.86 (m, 1H), 7.48-7.43 (m, 1H), 4.60-4.30(m, 1H), 3.78-3.15 (m, 2H), 2.78 (q, J=7.0 Hz, 2H), 2.68-2.62 (m, 2H),2.42-2.05 (m, 4H), 1.90-1.23 (m, 12H); MS (ESI+) m/z 354 (M+H); HPLC96.9% (AUC), t_(R)=11.90 min.

Example 22 Preparation of(S)—N-(1-Azabicyclo[2.2.2]oct-3-yl)-benzoxazole-4-carboxamideHydrochloride

Step A: A mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (300 mg,1.28 mmol), triethyl orthoformate (0.85 mL, 5.1 mmol), pyridiniump-toluenesulfonate (64 mg, 0.26 mmol) and xylenes (15 mL) was refluxedfor 4 h. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to afford thebenzoxazole-4-carboxylic acid (210 mg, quantitative) as a light yellowsolid: ¹H NMR (300 MHz, DMSO-d₆) δ 13.12 (s, 1H), 8.86 (s, 1H), 8.03(dd, J=8.1, 0.9 Hz, 1H), 7.92 (dd, J=8.1, 0.9 Hz, 1H), 7.54 (t, J=8.1Hz, 1H); MS (ESI+) m/z 164 (M+H).

Step B: A mixture of benzoxazole-4-carboxylic acid from Step A (110 mg,0.64 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (130 mg, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (245mg, 1.28 mmol), 1-hydroxybenzotriazole (173 mg, 1.28 mmol) and DMF (5mL) was stirred at room temperature for 5 min, then triethylamine (0.33mL, 2.6 mmol) was added. The resulting reaction mixture was stirred atroom temperature for 12 h. The mixture was diluted with dichloromethane(20 mL), and then washed with a saturated sodium bicarbonate (10 mL).The aqueous phase was further extracted with dichloromethane (3×15 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) toafford the carboxamide (140 mg, 80%) as a white solid: ¹H NMR (500 MHz,CDCl₃) δ 9.27 (d, J=5.0 Hz, 1H), 8.25-8.22 (m, 2H), 7.74 (d, J=8.0 Hz,1H), 7.53 (t, J=8.0 Hz, 1H), 4.33-4.22 (m, 1H), 3.55-3.43 (m, 1H),3.07-2.82 (m, 4H), 2.74 (dd, J=13.5, 4.5 Hz, 1H), 2.12-2.07 (m, 1H),2.00-1.91 (m, 1H), 1.80-1.68 (m, 2H), 1.60-1.51 (m, 1H); MS (ESI+) m/z272 (M+H).

Step C: To an ice-cold solution of the carboxamide from Step B (140 mg,0.52 mmol) in dichloromethane (2 mL) and ethyl ether (1 mL) was addedHCl (1 M solution in ethyl ether, 0.52 mL, 0.52 mmol). The mixture wasstirred at room temperature for 5 min, and then diluted with anhydrousethyl ether (20 mL). The mixture was left at room temperature for 2 h,and then the resulting precipitate was collected by filtration andwashed with ethyl ether (20 mL). The solid was dried on vacuum to afford(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-benzoxazole-4-carboxamidehydrochloride (68 mg, 43%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ10.24 (br s, 1H), 9.12 (d, J=6.5 Hz, 1H), 9.07 (s, 1H), 8.04 (dd, J=8.0,1.0 Hz, 1H), 7.95 (dd, J=8.0, 1.0 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H),4.42-4.37 (m, 1H), 3.78-3.70 (m, 1H), 3.40-3.15 (m, 5H), 2.28 (dd,J=6.0, 3.0 Hz, 1H), 2.19-2.10 (m, 1H), 1.98-1.85 (m, 3H); MS (ESI+) m/z272 (M+H); HPLC 92.1% (AUC), t_(R)=10.64 min.

Example 23 Preparation ofEndo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(1-acetylpiperidin-4-yl)benzoxazole-4-carboxamideHydrochloride

Step A: To a suspension of 2-amino-3-hydroxybenzoic acid hydrobromide(2.0 g, 8.5 mmol) in dichloromethane (25 mL) was added triethylamine(4.77 mL, 34.2 mmol) followed by 1-acetylpiperidine-4-carbonyl chloridehydrochloride (1.93 g, 8.55 mmol) at room temperature. The resultingreaction mixture was stirred at room temperature for 17 h. The reactionwas quenched with aqueous 2 N HCl (50 mL). The reaction mixture wasextracted with dichloromethane (3×250 mL). The combined organic phasewas dried (Na₂SO₄), filtered and concentrated to afford a light yellowsolid. The crude solid was dissolved in toluene (20 mL) and the solutionwas treated with p-toluenesulfonic acid monohydrate (2.08 g, 10.9 mmol).The reaction mixture was then heated to reflux under nitrogen for 10 h.The reaction was cooled to room temperature, poured into water (100 mL)and extracted with ethyl acetate (3×150 mL). The combined organic phasewas washed with water (2×100 mL), brine, dried (Na₂SO₄), filtered andconcentrated. The crude product was purified by column chromatography(silica gel, 9:1 to 7:3 ethyl acetate/methanol) to afford2-(1-acetylpiperidin-4-yl)benzoxazole-4-carboxylic acid (524 mg, 21%) asa brown solid: ¹H NMR (300 MHz, DMSO-d₆) δ 10.81 (br s, 1H), 7.48 (dd,J=7.7, 1.6 Hz, 1H), 6.94 (t, J=7.8 Hz, 1H), 6.89 (dd, J=7.7, 1.6 Hz,1H), 4.45-4.34 (m, 2H), 3.92-3.82 (m, 2H), 3.18-3.05 (m, 1H), 2.07-2.02(m, 2H), 2.02 (s, 3H), 1.92-1.82 (m, 2H); MS (ESI+) m/z 289 (M+H).

Step B: A mixture of 2-(1-acetylpiperidin-4-yl)benzoxazole-4-carboxylicacid (0.51 g, 1.77 mmol),endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (0.44 g,1.94 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(0.68 g, 3.54 mmol) and 1-hydroxybenzotriazole (0.48 g, 3.54 mmol) inDMF (10 mL) was stirred under nitrogen at room temperature for 10 min,and then triethylamine (1.47 mL, 10.6 mmol) was added. The resultingreaction mixture was stirred at room temperature for 17 h, quenched witha saturated aqueous solution of sodium bicarbonate (15 mL), and thenextracted with ethyl acetate (4×150 mL). The combined organic phase waswashed with water (4×150 mL), brine (3×150 mL), and dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 dichloromethane/methanol/concentratedammonium hydroxide) to afford the desired amide (300 mg, 40%) as anoff-white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.85 (d, J=6.5 Hz, 1H), 8.17(dd, J=7.9, 0.9 Hz, 1H), 7.61 (dd, J=7.9, 0.9 Hz, 1H), 7.43 (t, J=7.8Hz, 1H), 4.65-4.52 (m, 2H), 3.97-3.90 (m, 1H), 3.37-3.25 (m, 2H),3.18-3.10 (m, 2H), 3.02-2.95 (m, 1H), 2.65-2.57 (m, 2H), 3.55 (s, 3H),2.30-2.20 (m, 2H), 2.16 (s, 3H), 2.10-1.90 (m, 5H), 1.60-1.44 (m, 3H),1.22-1.14 (m, 2H); MS (ESI+) m/z 425 (M+H).

Step C: To a solution of the amide from step B (100 mg, 0.24 mmol) indichloromethane (0.5 mL) was slowly added a solution of HCl in diethylether (1.0 N, 0.26 mL, 0.26 mmol) at 0° C. The reaction mixture wasdiluted with diethyl ether (200 mL). The resulting solid was filteredand washed with diethyl ether (100 mL) to afford ofendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(1-acetylpiperidin-4-yl)benzoxazole-4-carboxamidehydrochloride (76 mg, 70%) as an off-white solid: ¹H NMR (500 MHz,CDCl₃) δ 12.27 (br s, 0.4H), 11.72 (br s, 0.6H), 9.24 (br s, 1H), 8.17(d, J=7.7 Hz, 0.4H), 8.11 (d, J=7.7 Hz, 0.6H), 7.69 (d, J=8.0 Hz, 0.4H),7.65 (d, J=8.0 Hz, 0.6H), 7.48 (t, J=7.8 Hz, 0.4H), 7.44 (t, J=7.8 Hz,0.6H), 4.87-4.54 (m, 2H), 4.03-3.90 (m, 1H), 3.67-3.35 (m, 2H),3.40-3.24 (m, 2H), 3.12-2.60 (m, 10H), 2.24-2.11 (m, 5H), 2.03-1.85 (m,2H), 1.84-1.55 (m, 4H); MS (ESI+) m/z 425 (M+H); HPLC >99% (AUC),t_(R)=13.96 min. Anal. Calcd for C₂₄H₃₂N₄O₃.HCl.1.5H₂O: C, 59.04; H,7.40; N, 11.41. Found: C, 59.12; H, 7.43; N, 11.46.

Example 24 Preparation ofEndo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(tetrahydro-2H-pyran-4-yl)benzoxazole-4-carboxamideHydrochloride

Step A: To an ice-cold suspension of tetrahydro-2H-pyran-4-carboxylicacid (0.65 g, 5.0 mmol) in dichloromethane (20 mL) was added oxalylchloride (0.47 mL, 5.0 mmol) dropwise followed by a few drops ofanhydrous DMF. After the ice-water bath was removed, the mixture wasstirred for 1 h. To the above solution was added2-amino-3-hydroxybenzoic acid hydrobromide (1.17 g, 5.0 mmol) followedby triethylamine (2.09 mL, 15.0 mmol). The resulting reaction mixturewas stirred at room temperature for 17 h. The reaction was quenched with1 N HCl (20 mL) and extracted with dichloromethane. The aqueous phasewas further extracted with dichloromethane (2×200 mL). The combinedorganic phase was washed with water (2×100 mL), dried (Na₂SO₄), filteredand concentrated to afford a light yellow solid. The crude solid wasdissolved in toluene (10 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (1.42 g, 7.46 mmol). The reactionmixture was then heated to reflux under nitrogen for 10 h. The reactionwas cooled to room temperature, poured into water and extracted withethyl acetate (2×250 mL). The organic phase was separated, washed withwater, brine, dried (Na₂SO₄), filtered and concentrated to afford the2-(tetrahydro-2H-pyran-4-yl)benzoxazole-4-carboxylic acid (590 mg, 49%)as a light brown solid: ¹H NMR (500 MHz, DMSO-d₆) δ 12.90 (br s, 1H),7.93 (dd, J=7.9, 1.0 Hz, 1H), 7.86 (dd, J=7.9, 1.0 Hz, 1H), 7.45 (t,J=7.9 Hz, 1H), 3.97-3.92 (m, 2H), 3.55-3.48 (m, 2H), 3.38-3.30 (m, 1H),2.07-2.02 (m, 2H), 1.92-1.82 (m, 2H); MS (ESI+) m/z 248 (M+H).

Step B: A mixture of the2-(tetrahydro-2H-pyran-4-yl)benzoxazole-4-carboxylic acid (290 mg, 1.17mmol), endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride(334 mg, 1.47 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (447 mg, 2.34 mmol) and 1-hydroxybenzotriazole (316 mg,2.34 mmol) in DMF (5 mL) was stirred under nitrogen at room temperaturefor 10 min, and then triethylamine (0.49 mL, 3.51 mmol) was added. Theresulting reaction mixture was stirred at room temperature for 17 h; thereaction was quenched with a saturated aqueous solution of sodiumbicarbonate (10 mL), and then extracted with ethyl acetate (3×150 mL).The combined organic phase was washed with brine and dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 dichloromethane/methanol/concentratedammonium hydroxide) to afford the desired amide (214 mg, 48%) as a whitesolid: ¹H NMR (500 MHz, CDCl₃) δ 8.95 (br s, 1H), 8.17 (dd, J=7.9, 0.8Hz, 1H), 7.74 (dd, J=7.9, 0.8 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 4.61-4.51(m, 1H), 4.15-4.08 (m, 2H), 3.65-3.60 (m, 2H), 3.32-3.26 (m, 1H),3.18-3.10 (m, 2H), 2.65-2.55 (m, 5H), 2.17-1.95 (m, 7H), 1.56-1.42 (m,3H), 1.18-1.09 (m, 2H); MS (ESI+) m/z 384 (M+H).

Step C: To a solution of the amide from step B (208 mg, 0.54 mmol) inmethanol (1.5 mL) was slowly added a solution of HCl in diethyl ether (1N, 0.6 mL, 0.6 mmol) at 0° C. The reaction mixture was diluted withdiethyl ether (200 mL). The resulting solid was filtered and washed withdiethyl ether (150 mL) to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(tetrahydro-2H-pyran-4-yl))benzoxazole-4-carboxamidehydrochloride (186 mg, 82%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ12.30 (br s, 0.4H), 11.83 (br s, 0.6H), 9.6 (d, J=4.6 Hz, 0.4H),9.33-9.28 (m, 0.6H), 8.15 (d, J=7.8 Hz, 0.4H), 8.11 (d, J=7.8 Hz, 0.6H),7.68 (d, J=8.0 Hz, 0.4H), 7.65 (d, J=8.0 Hz, 0.6H), 7.47 (t, J=8.0 Hz,0.4H), 7.43 (t, J=8.0 Hz, 0.6H), 4.84-4.74 (m, 0.6H), 4.62-4.52 (m,0.4H), 4.15-4.07 (m, 2H), 3.64-3.53 (m, 4H), 3.37-3.24 (m, 1H),3.00-2.60 (m, 7H), 2.27-2.05 (m, 6H), 1.95-1.67 (m, 4H); MS (ESI+) m/z384 (M+H); HPLC 98.5% (AUC), t_(R)=14.81 min. Anal. Calcd forC₂₂H₂₉N₃O₃.HCl.0.5H₂O: C, 61.60; H, 7.28; N, 9.80. Found: C, 61.45; H,7.35; N, 9.73.

Example 25 Preparation of(S)—N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(tetrahydro-2H-pyran-4-yl)benzoxazole-4-carboxamideHydrochloride

Step A: A mixture of2-(tetrahydro-2H-pyran-4-yl)benzoxazole-4-carboxylic acid (290. mg, 1.17mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (447mg, 2.34 mmol), 1-hydroxybenzotriazole (316 mg, 2.34 mmol) and(S)-(−)-3-aminoquinuclidine dihydrochloride (293 mg, 1.47 mmol) in DMF(5 mL) was stirred at room temperature for 10 min, then triethylamine(0.49 mL, 3.51 mmol) was added. The resulting reaction mixture wasstirred at room temperature 17 h. The reaction mixture was diluted withethyl acetate (50 mL), and then treated with a saturated aqueoussolution of sodium bicarbonate (10 mL). The organic layer was isolatedand the aqueous layer was further extracted with ethyl acetate (3×200mL). The combined organics were washed with water (3×100 mL) and brine(2×100 mL), dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford thedesired amide (221 mg, 53%) as an off-white solid: ¹H NMR (500 MHz,CDCl₃) δ 9.45 (d, J=7.2 Hz, 1H), 8.15 (dd, J=7.9, 0.9 Hz, 1H), 7.63 (dd,J=7.9, 0.9 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 4.32-4.25 (m, 1H), 4.12-4.06(m, 2H), 3.66-3.58 (m, 2H), 3.52-3.45 (m, 1H), 3.30-3.25 (m, 1H),3.03-2.96 (m, 2H), 2.94-2.85 (m, 2H), 2.78-2.73 (m, 1H), 2.20-2.12 (m,2H), 2.10-1.95 (m, 4H), 1.78-1.73 (m, 2H), 1.66-1.55 (m, 1H); MS (ESI+)m/z 356 (M+H).

Step B: To a solution of the amide from Step A (217 mg, 0.61 mmol) inmethanol (1.5 mL) was slowly added a solution of HCl in diethyl ether (1N, 0.67 mL, 0.67 mmol) at 0° C. The reaction mixture was diluted withdiethyl ether (200 mL). The resulting solid was filtered and washed withdiethyl ether (250 mL) to afford(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(tetrahydro-2H-pyran-4-yl)benzoxazole-4-carboxamidehydrochloride (206 mg, 83%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ12.70 (br s, 1H), 9.47 (d, J=7.2 Hz, 1H), 8.13 (d, J=7.7 Hz, 1H), 7.69(d, J=7.9 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 4.68-4.62 (m, 1H), 4.18-4.10(m, 2H), 3.79 (t, J=10.2 Hz, 1H), 3.62 (t, J=11.3 Hz, 2H), 3.45-3.18 (m,6H), 2.55-2.50 (m, 1H), 2.35-2.28 (m, 1H), 2.15-1.95 (m, 6H), 1.75-1.65(m, 1H); MS (ESI+) m/z 356 (M+H); HPLC 98.6% (AUC), t_(R)=13.32 min.

Anal. Calcd for C₂₀H₂₅N₃O₃.HCl.0.5H₂O: C, 59.92; H, 6.79; N, 10.48; Cl,8.84. Found: C, 59.61; H, 6.95; N, 10.49; Cl, 8.83.

Example 26 Preparation ofEndo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(quinuclidin-4-yl)benzoxazole-4-carboxamideDihydrochloride

Step A: A mixture of 4-cyano-quinuclidine (0.95 g, 6.97 mmol), andmethylene chloride (20 mL) was stirred, and cooled to −78° C.Diisobutylaluminum hydride (1 M solution in hexanes, 17.4 mmol, 17.4 mL)was added dropwise to the reaction mixture and stirring continued 2 h.The reaction was quenched with a saturated aqueous solution ofRochelle's salt (sodium potassium tartrate 10 mL) and the reaction wasallowed to warm to room temperature. The aqueous phase was extractedwith methylene chloride (2×20 mL), the combined organic phase was washedwith water and dried (Na₂SO₄), concentrated to afforded crudequinuclidine-4-carbaldehyde as a white solid (0.57 g, 55%). The crudeproduct was used without further purification: ¹H NMR (500 MHz, CDCl₃) δ9.38 (s, 1H), 2.96-2.92 (m, 6H), 1.62-1.53 (m, 6H).

Step B: A mixture of quinuclidine-4-carbaldehyde (0.57 g, 4.10 mmol),piperidine (0.86 g, 1 mL, 10.10 mmol), methyl 2-amino-3-hydroxybenzoate(0.68 g, 4.10 mmol) and methanol (10 mL) was heated to reflux for 40 h.Analysis by LCMS indicated the presence of the requisite intermediateSchiff base. The solvent was removed under reduced pressure, the residuewas dissolved in methylene chloride (20 ml) and silver (I) oxide (1.23g, 5.34 mmol) was added. The reaction mixture was stirred at roomtemperature for 5 h. Analysis by LCMS indicated consumption of theSchiff base intermediate. The reaction mixture was filtered thoughdiatomaceous earth (10 g) eluting with methylene chloride (50 mL) andconcentrated. The crude product was purified by column chromatography(silica gel, 5 to 20% methanol in chloroform) to afford methyl2-(quinuclidin-4-yl)benzoxazole-4-carboxylate (250 mg, 17%) as an brownsolid: ¹H NMR (300 MHz, CDCl₃) δ 7.96 (dd, J=8.0, 1.0 Hz, 1H), 7.67 (dd,J=8.0, 1.0 Hz, 1H), 7.37 (d, d, J=8.0 Hz, 1H), 4.01 (s, 3H), 3.06-3.02(m, 6H), 2.06-2.01 (m, 6H); MS (ESI+) m/z 287 (M+H).

Step C: A mixture of methyl2-(quinuclidin-4-yl)benzoxazole-4-carboxylate (233 mg, 0.81 mmol),lithium hydroxide monohydrate (51 mg, 1.22 mmol) and THF/water (2:1, 15mL) was stirred at room temperature for 6 h. The reaction mixture wasconcentrated, and washed with brine (10 mL), the precipitate whichformed was filtered, washed with hexanes and dried to afford2-(quinuclidin-4-yl)benzoxazole-4-carboxylic acid (240 mg, 108%) as abrown solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.80 (d, J=8.0 Hz, 1H), 7.67(d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 2.83-2.81 (m, 6H), 1.89-1.84(m, 6H); MS (ESI+) m/z 273 (M+H).

Step D: A mixture of 2-(quinuclidin-4-yl)benzoxazole-4-carboxylic acid(221 mg, 0.81 mmol), endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (221 mg, 0.97 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (311 mg,1.62 mmol), 1-hydroxybenzotriazole (219 mg, 1.62 mmol) and DMF (5 mL)was stirred at room temperature for 5 min, then triethylamine (0.47 mL,3.40 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 40 h. The mixture was diluted with ethyl acetate (30mL), and then washed with a saturated sodium bicarbonate (10 mL). Theaqueous phase was further extracted with dichloromethane (3×15 mL). Thecombined organic phase was dried (Na₂SO₄), filtered and concentrated.The crude material was purified by column chromatography (silica gel,100% dichloromethane to 100% 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford therequisite carboxamide (94 mg, 28%) as an off-white solid: ¹H NMR (500MHz, CDCl₃) δ 8.99 (d, J=7.0 Hz, 1H), 8.16 (dd, J=8.0, 1.0 Hz, 1H),7.65-7.57 (m, 1H), 7.40 (t, J=8.0 Hz, 1H), 4.53-4.51 (m, 1H), 3.15-3.05(m, 7H), 2.63-2.53 (m, 2H), 2.51 (s, 3H), 2.15-1.95 (m, 7H) 1.72-1.50(m, 4H), 1.50-1.38 (m, 2H), 1.16-1.04 (m, 2H); MS (ESI+) m/z 409 (M+H).

Step E: To an ice-cold solution of the carboxamide from Step D (94 mg,0.23 mmol) in dichloromethane (3 mL) was added HCl (1 M solution inethyl ether, 0.69 mL, 0.69 mmol). The mixture was stirred at roomtemperature for 1 h, and then diluted with anhydrous ethyl ether (20mL). The mixture was left at room temperature for 1 h, and then theresulting precipitate was collected by filtration and washed with ethylether (20 mL). The solid was dried under vacuum to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(quinuclidin-4-yl)benzoxazole-4-carboxamidedihydrochloride (90 mg, 77%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆)δ 10.82-10.70 (m, 1.3H), 10.02-9.90 (br s, 0.5H), 9.07-9.05 (m, 0.4H),8.82-8.70 (m, 0.6H), 8.00-7.90 (m, 2H), 7.60-7.52 (m, 1H), 4.64-4.56 (m,0.6H), 4.42-4.36 (m, 0.4H), 3.68-3.60 (m, 1H), 3.58-3.52 (m, 1H),3.48-3.38 (m, 6H), 2.83 (s, 3H), 2.76-2.60 (m, 2H), 2.38-2.20 (m, 7H),2.18-2.06 (m, 2H), 1.88-1.72 (m, 3H), 1.68-1.44 (m, 2H); MS (ESI+) m/z408 (M+H); HPLC 98.3% (AUC), t_(R)=12.93 min. Anal. Calcd forC₂₄H₃₂N₄O₂.1.75HCl.2H₂O: C, 56.70; H, 7.48; N, 11.02.

Found: C, 56.88; H, 7.38; N, 11.12.

Example 27 Preparation ofEndo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(piperidin-4-yl)benzoxazole-4-carboxamideDihydrochloride

Step A: A mixture of 1-(tert-butoxycarbonyl)piperidin-4-carboxylic acid(2.47 g, 10.78 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (3.43 g, 17.96 mmol), 1-hydroxybenzotriazole (2.42 g,17.96 mmol) and methyl 2-amino-3-hydroxybenzoate (1.50 g, 8.98 mmol) indichloromethane (25 mL) was stirred under nitrogen at room temperaturefor 10 min, and then triethylamine (1.47 mL, 10.6 mmol) was added. Theresulting reaction mixture was stirred at room temperature for 5 h, thereaction was quenched with a saturated aqueous solution of sodiumbicarbonate (15 mL), and then extracted with dichloromethane (2×150 mL).The combined organic phase was washed with water (2×100 mL), brine(2×100 mL), and dried (Na₂SO₄), filtered and concentrated to afford alight yellow solid. The crude solid was dissolved in toluene (20 mL) andthe solution was treated with p-toluenesulfonic acid monohydrate (2.08g, 10.9 mmol). The reaction mixture was then heated to reflux undernitrogen for 4 h. The reaction was cooled to room temperature andconcentrated. The crude product was purified by column chromatography(silica gel, 90:9:1 dichloromethane/methanol/concentrated ammoniumhydroxide) to afford 2-(piperidin-4-yl)benzoxazole-4-carboxylate methylester (1.64 mg, 70%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ7.99 (dd, J=7.8, 0.9 Hz, 1H), 7.78 (dd, J=7.8, 0.9 Hz, 1H), 7.39 (t,J=7.8 Hz, 1H), 4.00 (s, 3H), 3.52-3.45 (m, 2H), 3.36-3.30 (m, 1H)3.10-3.03 (m, 2H), 2.33-2.20 (m, 4H); MS (ESI+) m/z 261 (M+H).

Step B: A mixture of the 2-(piperidin-4-yl)benzoxazole-4-carboxylatemethyl ester (1.64 g, 6.3 mmol), di-tert-butyldicarbonate (1.72 g, 7.87mmol) and DMAP (153 mg, 1.26 mmol) in dichloromethane (50 mL) wasstirred at room temperature for 3 h, the reaction was quenched with asaturated aqueous solution of sodium bicarbonate (10 mL), and thenextracted with dichloromethane (2×100 mL). The combined organic phasewas washed with water (2×75 mL), brine (2×75 mL), and dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 3:2, hexanes/ethyl acetate) to afford2-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoxazole-4-carboxylatemethyl ester (1.30 g, 58%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ7.98 (dd, J=7.8, 0.9 Hz, 1H), 7.69 (dd, J=7.8, 0.9 Hz, 1H), 7.38 (t,J=7.8 Hz, 1H), 4.26-4.22 (m, 2H), 4.02 (s, 3H), 3.30-3.18 (m, 1H)3.00-2.90 (m, 2H), 2.20-2.10 (m, 2H), 2.03-1.90 (m, 2H), 1.48 (s, 9H);MS (ESI+) m/z 361 (M+H

Step C: A mixture of the2-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoxazole-4-carboxylatemethyl ester (1.30 g, 3.60 mmol) was treated with lithium hydroxide monohydrate (0.23 g, 5.42 mmol) in a mixture of tetrahydrofuran (15 mL) andwater (5 mL). The reaction mixture was stirred under nitrogen at roomtemperature for 6 h, cooled to 0° C., adjusted to pH 6, and thenextracted with dichloromethane (4×150 mL). The combined organic phasewas washed with water (4×150 mL), brine (3×150 mL), and dried (Na₂SO₄),filtered and concentrated to afford the desired acid (1.20 g, 96%) as awhite solid: ¹H NMR (500 MHz, CDCl₃) δ 7.98 (dd, J=7.8, 0.9 Hz, 1H),7.69 (dd, J=7.8, 0.9 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 4.30-4.15 (m, 2H),3.26-3.18 (m, 1H) 3.10-2.90 (m, 2H), 2.25-2.15 (m, 2H), 1.95-1.85 (m,2H), 1.49 (s, 9H), 1.40-1.20 (m, 2H); MS (ESI+) m/z 347 (M+H).

Step D: A mixture of the2-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoxazole-4-carboxylic acid(0.60 g, 1.73 mmol), endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (0.47 g, 2.08 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.66 g,3.46 mmol) and 1-hydroxybenzotriazole (0.47 g, 3.46 mmol) in DMF (10 mL)was stirred under nitrogen at room temperature for 10 min, and thentriethylamine (0.72 mL, 5.19 mmol) was added. The resulting reactionmixture was stirred at room temperature for 17 h, quenched with asaturated aqueous solution of sodium bicarbonate (15 mL), and thenextracted with ethyl acetate (4×200 mL). The combined organic phase waswashed with water (4×200 mL), brine (3×150 mL), and dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 dichloromethane/methanol/concentratedammonium hydroxide) to afford the desired amide (480 mg, 57%) as anoff-white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.93 (br s, 1H), 8.17 (d,J=7.8 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 4.65-4.50(m, 1H), 4.25-4.10 (m, 2H), 3.25-3.00 (m, 5H), 2.75-2.50 (m, 5H),2.25-1.90 (m, 7H), 1.64-1.50 (m, 3H), 1.47 (s, 9H); MS (ESI+) m/z 483(M+H).

Step E: To a solution of the amide from step D (471 mg, 0.98 mmol) indichloromethane (0.5 mL) added a solution of HCl in dioxane dropwise(4.0 N, 1.23 mL, 4.90 mmol) at 0° C. and stirred for 2 h. The reactionmixture was concentrated and dissolved in methanol (5 mL), and thendiluted with diethyl ether (250 mL). The resulting solid was filteredand washed with diethyl ether (300 mL) to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(piperidin-4-yl)benzoxazole-4-carboxamidedihydro chloride (306 mg, 69%) as a white solid: ¹H NMR (500 MHz,DMSO-d₆) δ 10.54 (br s, 0.4H), 9.80 (br s, 0.6H), 9.22 (br s, 0.6H),9.15 (br s, 0.4H), 9.11 (d, J=5.3 Hz, 0.4H), 8.83 (d, J=6.6 Hz, 0.6H),8.00-7.90 (m, 2H), 7.60-7.50 (m, 1H), 4.65-4.55 (m, 0.6H), 4.45-4.35 (m,0.4H), 3.70-3.62 (m, 1H), 3.60-3.50 (m, 2H), 3.47-3.40 (m, 2H),3.40-3.24 (m, 2H), 3.15-3.05 (m, 2H), 2.85-2.80 (m, 3H), 2.75-2.60 (m,2H), 2.35-2.23 (m, 3H), 2.20-2.05 (m, 4H), 1.85-1.75 (m, 2H), 1.55-1.49(m, 2H); MS (ESI+) m/z 383 (M+H); HPLC >99% (AUC), t_(R)=11.28 min.Anal. Calcd for C₂₂H₃₀N₄O₂.2.2HCl.0.5H₂O: C, 56.02; H, 7.02; N, 11.88;Cl, 16.53. Found: C, 56.33; H, 7.39; N, 11.84; C, 16.13.

Example 28 Preparation of(S)—N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(piperidin-4-yl)benzoxazole-4-carboxamideDihydrochloride

Step A: A mixture of2-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoxazole-4-carboxylic acid(0.60 g, 1.73 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (66 g, 3.46 mmol), 1-hydroxybenzotriazole (0.47 g, 3.46mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (0.41 g, 2.08mmol) in DMF (10 mL) was stirred at room temperature for 10 min, thentriethylamine (0.72 mL, 5.19 mmol) was added. The resulting reactionmixture was stirred at room temperature 17 h. The reaction mixture wasdiluted with ethyl acetate (50 mL), and then treated with a saturatedaqueous solution of sodium bicarbonate (20 mL). The organic phase wasseparated and the aqueous layer was further extracted with ethyl acetate(3×200 mL). The combined organics were washed with water (3×100 mL) andbrine (2×100 mL), dried (Na₂SO₄), filtered and concentrated. The crudematerial was purified by column chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford thedesired amide (361 mg, 50%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ9.43 (d, J=7.4 Hz, 1H), 8.15 (dd, J=7.7, 0.9 Hz, 1H), 7.63 (dd, J=7.7,0.9 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 4.38-4.28 (m, 1H), 4.20-4.10 (m,2H), 3.55-3.47 (m, 1H), 3.25-3.15 (m, 1H), 3.10-2.90 (m, 6H), 2.85-2.75(m, 1H), 2.26-2.12 (m, 3H), 2.05-1.60 (m, 6H), 1.49 (s, 9H); MS (ESI+)m/z 455 (M+H).

Step B: To a solution of the amide from Step A (60 mg, 0.13 mmol) indichloromethane (1.0 mL) was slowly added a solution of HCl in dioxane(4 N, 0.33 mL, 1.32 mmol) and stirred at 0° C. for 1 h The reactionmixture was concentrated dissolved in methanol (2 mL) and then dilutedwith diethyl ether. The resulting solid was filtered and washed withdiethyl ether (300 mL) to afford(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(piperidin-4-yl)benzoxazole-4-carboxamidedihydrochloride (41 mg, 71%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆)δ 10.46 (br s, 1H), 9.21 (d, J=6.5 Hz, 1H), 9.09 (br s, 1H), 7.96 (d,J=7.9 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 4.46-4.40(m, 1H), 3.75 (t, J=10.2 Hz, 1H), 3.58-3.50 (m, 1H), 3.40-3.34 (m, 3H),3.30-3.20 (m, 2H), 3.19-3.08 (m, 4H), 2.40-2.26 (m, 4H), 2.21-2.10 (m,3H), 1.97-1.88 (m, 3H); MS (ESI+) m/z 355 (M+H); HPLC >99% (AUC),t_(R)=14.24 min. Anal. Calcd for C₂₀H₂₆N₄O₂.2.5HCl.2.5H₂O: C, 49.03; H,6.87; N, 11.40. Found: C, 49.05; H, 6.65; N, 11.31.

Example 29 Preparation ofEndo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(1-methylpiperidin-4-yl)benzoxazole-4-carboxamideDihydrochloride

Step A: To a solution ofendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(piperidin-4-yl)benzoxazole-4-carboxamide(79 mg, 0.2 mmol) in methanol (3 mL) was added 37% formaldehyde (0.05mL, 0.6 mmol) at room temperature. The resulting mixture was stirred for17 h. To the above solution was added sodium borohydride (40 mg, 1.0mmol) at 0° C. The resulting reaction mixture was stirred at roomtemperature for 3 h. The reaction was quenched with water (2 mL) andextracted with dichloromethane (3×50 mL). The combined organic phase waswashed with water (2×20 mL), dried (Na₂SO₄), filtered and concentratedto afford an off-white solid. The crude material was purified by columnchromatography (silica gel, 90:9:1 dichloromethane/methanol/concentratedammonium hydroxide) to afford the desired amide (68 mg, 82%) as a whitesolid: ¹H NMR (500 MHz, CDCl₃) δ 8.95 (d, J=7.2 Hz, 1H), 8.16 (dd,J=7.8, 0.9 Hz, 1H), 7.59 (dd, J=7.8, 0.9 Hz, 1H), 7.43 (t, J=8.0 Hz,1H), 4.58-4.50 (m, 1H), 3.12-3.07 (m, 2H), 3.02-2.95 (m, 2H), 2.64-2.55(m, 2H), 3.52 (s, 3H), 2.35 (s, 3H), 2.25-2.15 (m, 4H), 2.12-1.95 (m,5H), 1.65-1.54 (m, 2H), 1.45-1.38 (m, 2H), 1.15-1.10 (m, 2H); MS (ESI+)m/z 397 (M+H).

Step B: To a solution of the amide from step A (68 mg, 0.17 mmol) indichloromethane (2 mL) was slowly added a solution of HCl in diethylether (1 N, 0.36 mL, 0.36 mmol) at 0° C. The reaction mixture wasdiluted with diethyl ether (100 mL). The resulting solid was filteredand washed with diethyl ether (150 mL) to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(1-methylpiperidin-4-yl)benzoxazole-4-carboxamidedihydrochloride (63 mg, 79%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆)δ 11.04 (br s, 1H), 10.53 (br s, 0.4H), 9.79 (br s, 0.6H), 9.14 (br s,0.4H), 8.87 (br s, 0.6H), 8.02-7.90 (m, 2H), 7.60-7.50 (m, 1H),4.65-4.55 (m, 0.6H), 4.42-4.35 (m, 0.4H), 3.70-3.35 (m, 6H), 3.20-3.04(m, 2H), 2.83 (s, 3H), 2.78-2.58 (m, 5H), 2.41-2.05 (m, 7H), 1.90-1.73(m, 2H), 1.68-1.45 (m, 2H); MS (ESI+) m/z 397 (M+H); HPLC >99% (AUC),t_(R)=12.06 min. Anal. Calcd for C₂₃H₃₂N₄O₂.2HCl. 3H₂O: C, 52.77; H,7.70; N, 10.70. Found: C, 52.60; H, 7.66; N, 10.60.

Example 30 Preparation of(S)—N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(1-methylpiperidin-4-yl)benzoxazole-4-carboxamideDihydrochloride Dihydrochloride

Step A: To a solution ofendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(piperidin-4-yl)benzoxazole-4-carboxamide(78 mg, 0.21 mmol) in methanol (3 mL) was added 37% formaldehyde (0.05mL, 0.6 mmol) at room temperature. The resulting mixture was stirred for17 h. To the above solution was added sodium borohydride (42 mg, 1.1mmol) at 0° C. The resulting reaction mixture was stirred at roomtemperature for 3 h. The reaction was quenched with water (2 mL) andextracted with dichloromethane (3×50 mL). The combined organic phase waswashed with water (2×20 mL), dried (Na₂SO₄), filtered and concentratedto afford an off-white solid. The crude material was purified by columnchromatography (silica gel, 90:9:1 dichloromethane/methanol/concentratedammonium hydroxide) to afford the desired methylated amine (56 mg, 72%)as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.51 (d, J=7.3 Hz, 1H), 8.15(dd, J=7.9, 0.9 Hz, 1H), 7.62 (dd, J=7.9, 0.9 Hz, 1H), 7.42 (t, J=8.0Hz, 1H), 4.28-4.23 (m, 1H), 3.50-3.45 (m, 1H), 3.10-2.85 (m, 7H),2.78-2.72 (m, 1H), 2.34 (s, 3H), 2.27-2.17 (m, 4H), 2.10-1.95 (m, 4H),1.76-1.70 (m, 2H), 1.60-1.52 (m, 1H); MS (ESI+) m/z 369 (M+H).

Step B: To a solution of the amine from Step A (56 mg, 0.15 mmol) inmethanol (1.5 mL) was slowly added a solution of HCl in diethyl ether (1N, 0.32 mL, 0.32 mmol) at 0° C. The reaction mixture was diluted withdiethyl ether (150 mL). The resulting solid was filtered and washed withdiethyl ether (100 mL) to afford(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(1-methylpiperidin-4-yl)benzoxazole-4-carboxamidedihydrochloride (63 mg, 86%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆)δ 10.96 (br s, 0.7H), 10.71, (br s, 0.3H), 10.28 (br s, 1H), 9.25 (d,J=7.7 Hz, 1H), 7.97 (d, J=7.7 Hz, 1H), 7.91 (d, J=7.7 Hz, 1H), 7.47 (t,J=8.0 Hz, 1H), 4.46-4.40 (m, 1H), 3.75 (t, J=11.9 Hz, 1H), 3.55-3.35 (m,5H), 3.30-3.10 (m, 6H), 2.76 (s, 3H), 2.45-2.35 (m, 2H), 2.30-2.10 (m,3H), 2.00-1.95 (m, 3H); MS (ESI+) m/z 369 (M+H); HPLC 97.9% (AUC),t_(R)=11.66 min. Anal. Calcd for C₂₁H₂₈N₄O₂.2HCl. 2.5H₂O: C, 51.78; H,7.25; N, 11.52. Found: C, 51.61; H, 7.17; N, 11.79.

Example 31 Preparation of(S)—N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(1-acetylpiperidin-4-yl)benzoxazole-4-carboxamideHydrochloride

Step A: To a slurry of(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(piperidin-4-yl)benzoxazole-4-carboxamide(35 mg. 0.1 mmol) in acetonitrile (3 mL) was added cesium carbonate (40mg, 0.30 mmol). The resulting reaction mixture was stirred at roomtemperature for 30 min, and then acetyl chloride (0.03 mL, 0.4 mmol) wasadded. The resulting reaction mixture was stirred at room temperaturefor 17 h. The reaction was quenched with water (2 mL), and thenextracted with dichloromethane (3×50 mL). The combined organics werewashed with brine (1×25 mL), dried (Na₂SO₄), filtered and concentrated.The crude material was purified by preparative TLC (90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford thedesired amide (31 mg, 77%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ9.38 (d, J=7.4 Hz, 1H), 8.16 (dd, J=7.7, 0.9 Hz, 1H), 7.64 (dd, J=7.7,0.9 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 4.65-4.55 (m, 1H), 4.30-4.22 (m,1H), 4.00-3.95 (m, 1H), 3.55-3.20 (m, 3H), 3.05-2.95 (m, 5H), 2.85-2.75(m, 1H), 2.26-2.12 (m, 3H), 2.15 (s, 3H), 2.10-1.85 (m, 4H), 1.75-1.65(m, 2H); MS (ESI+) m/z 397 (M+H).

Step B: To a solution of the amide from Step A (31 mg, 0.08 mmol) inmethanol (1.0 mL) was slowly added HCl (1 N in diethyl ether, 0.16 mL,0.16 mmol) and stirred at 0° C. for 1 h. The compound mixture wasconcentrated and purified by reverse phase HPLC (100% water containing0.05% trifluoroacetic acid (TFA) and 100% water containing 0.05% TFA).The solid obtained was treated with a solution of HCl in diethyl ether(1 N, 0.04 mL, 0.04 mmol) to afford(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(1-acetylpiperidin-4-yl)benzoxazole-4-carboxamidehydrochloride (16 mg, 47%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ10.00 (br s, 1H), 9.28 (d, J=7.4 Hz, 1H), 7.96 (d, J=7.7, Hz, 1H), 7.90(d, J=7.7 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 4.45-4.38 (m, 1H), 4.30-4.25(m, 1H), 3.90-3.82 (m, 1H), 3.75 (t, J=11.0 Hz, 1H), 3.48-3.40 (m, 1H),3.35-3.15 (m, 6H), 3.00-2.90 (m, 1H), 2.30-2.12 (m, 4H), 2.03 (s, 3H),2.00-1.65 (m, 5H); MS (ESI+) m/z 397 (M+H); HPLC 95.2% (AUC),t_(R)=14.24 min.

Example 32 Preparation ofN-(9-methyl-3-oxa-9-azabicyclo[3.3.1]non-7-yl)-2-(cyclopentyl-4-yl)benzoxazole-4-carboxamideHydrochloride

Step A: A mixture of the 2-cyclopentylbenzoxazole-4-carboxylic acid (70mg, 0.30 mmol), 7-amino-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonanedihydrochloride (83 mg, 0.36 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg,0.60 mmol) and 1-hydroxybenzotriazole (81 mg, 0.60 mmol) in DMF (4 mL)was stirred under nitrogen at room temperature for 10 min, and thentriethylamine (0.15 mL, 1.20 mmol) was added. The resulting reactionmixture was stirred at room temperature for 17 h. The reaction wasquenched with a saturated aqueous solution of sodium bicarbonate (10mL), and then extracted with ethyl acetate (3×50 mL). The combinedorganic phase was washed with water (2×50 mL) brine (1×50 mL) and dried(Na₂SO₄), filtered and concentrated. The crude material was purified bycolumn chromatography (silica gel, 90:9:1dichloromethane/methanol/concentrated ammonium hydroxide) to afford thedesired amide (63 mg, 57%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ9.95 (d, J=8.9 Hz, 1H), 8.09 (dd, J=7.8, 1.0 Hz, 1H), 7.56 (dd, J=7.8,1.0 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 4.86-4.75 (m, 1H), 4.00-3.92 (m,2H), 3.87-3.82 (m, 2H), 2.70-2.65 (m, 2H), 2.60-2.50 (m, 5H), 2.20-2.05(m, 4H), 1.90-1.70 (m, 5H), 1.65-1.56 (m, 2H); MS (ESI+) m/z 370 (M+H).

Step B: To a solution of the amide from step B (63 mg, 0.17 mmol) indichloromethane (1.5 mL) was slowly added a solution of HCl in diethylether (1 N, 0.19 mL, 0.6 mmol) at 0° C. The reaction mixture was dilutedwith diethyl ether (200 mL). The resulting solid was filtered and washedwith diethyl ether (300 mL) to affordN-(9-methyl-3-oxa-9-azabicyclo[3.3.1]non-7-yl)-2-(cyclopentyl-4-yl)benzoxazole-4-carboxamidehydrochloride (61 mg, 83%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ11.28 (br s, 0.6H), 10.82 (br s, 0.4H), 9.82-9.75 (m, 1H), 7.94 (d,J=7.8 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 4.70-4.64(m, 1H), 4.30-4.20 (m, 2H), 4.08-4.02 (m, 1.2H), 3.90-3.84 (m, 0.8H),3.52-3.42 (m, 3H), 3.05-3.00 (m, 1H), 2.90-2.87 (m, 2H), 2.86-2.82 (m,0.8H), 2.75-2.65 (m, 1.2H), 2.18-2.10 (m, 2H), 2.08-2.00 (m, 3H),1.83-1.65 (m, 5H); MS (ESI+) m/z 370 (M+H); HPLC 98.4% (AUC),t_(R)=15.85 min.

Example 33 Preparation ofEndo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1-methylpiperidin-2-yl)benzoxazole-4-carboxamideHydrochloride

Step A: A mixture of 1-methylpiperidine-2-carboxylic acid hydrochloride(0.57 g, 3.17 mmol), methyl 2-amino-3-hydroxybenzoate (0.64 g, 3.80mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.26g, 6.34 mmol), 1-hydroxybenzotriazole (0.85 g, 6.34 mmol) and DMF (20mL) was stirred at room temperature for 5 min, thendiisopropylethylamine (1.46 mL, 8.88 mmol) was added. The resultingreaction mixture was stirred at room temperature for 17 h. The mixturewas diluted with ethyl acetate (10 mL), and then washed with saturatedsodium bicarbonate (10 mL). The aqueous phase was further extracted withethyl acetate (3×40 mL). The combined organic phase was washed withbrine (10 mL), dried (Na₂SO₄), filtered and concentrated. The crudeproduct (a mixture of 2-amino-3-(methoxycarbonyl)phenyl1-methylpiperidine-2-carboxylate and methyl3-hydroxy-2-(1-methylpiperidine-2-carboxamido)benzoate) was directlyelaborated in step B: MS (ESI+) m/z 293 (M+H).

Step B: The crude product mixture from Step A (0.46 g, 1.59 mmol) wasdissolved in toluene (20 mL) and the solution was treated withmethanesulfonic acid monohydrate (2.08 g, 10.9 mmol). The reactionmixture was then heated to reflux using a Dean-Stark Trap containing 4 Åmolecular sieves under nitrogen for 174 h. The reaction was cooled toroom temperature and concentrated partitioned between saturated sodiumbicarbonate (10 ml) and ethyl acetate (50 mL), the aqueous phase wasfurther extracted with ethyl acetate (3×30 mL), washed with 5% lithiumchloride solution, brine, dried (Na₂SO₄), filtered and concentrated. Thecrude product was purified by column chromatography (silica gel, 20 to100% ethyl acetate in hexanes) to afford methyl2-(1-methylpiperidin-2-yl)benzoxazole-4-carboxylate (233 mg, 54%) as anoff-white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.00 (d, J=13.0 Hz, 1H), 7.74(d, J=13.0 Hz, 1H), 4.02 (s, 3H), 3.60 (dd, J=17.2, 6.0 Hz, 1H),3.12-3.06 (m, 1H), 2.30-2.26 (m, 4H), 2.08-1.80 (m, 3H), 1.78-1.60 (m,2H), 1.48-1.30 (m, 2H); MS (ESI+) m/z 275 (M+H).

Step C: A mixture ofmethyl-2(1-methylpiperidin-2-yl)-benzoxazole-4-carboxylate (0.33 g, 1.21mmol), lithium hydroxide monohydrate (153 mg, 3.64 mmol) andmethanol/water (3:1, 12 mL) was stirred at room temperature for 17 h.The reaction mixture was cooled to 0° C. and treated with HCl (1.0 Msolution in diethyl ether, 4.30 mL, 4.30 mmol). The solvent was removedunder vacuum and the crude2(1-methylpiperidin-2-yl)-benzoxazole-4-carboxylic acid directlyelaborated without further purification: MS (ESI+) m/z 261 (M+H).

Step D: A mixture of the carboxylic acid product from Step C (310 mg,1.21 mmol), endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (330 mg, 1.45 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.48 g,2.42 mmol), 1-hydroxybenzotriazole (0.33 g, 2.42 mmol) and DMF (10 mL)was stirred at room temperature for 5 min, then triethylamine (0.50 mL,3.63 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 17 h. The mixture was diluted with ethyl acetate (10mL), and then washed with saturated sodium bicarbonate (10 mL). Theaqueous phase was further extracted with ethyl acetate (3×40 mL). Thecombined organic phase was washed with brine (10 mL), dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 100% 9:1 dichloromethane/methanol to 100%90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) toaffordendo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1-methylpiperidin-2yl)benzoxazole-4-carboxamide(189 mg, 36%) as a off-white solid and as a mixture of enantiomers: ¹HNMR (500 MHz, CDCl₃) δ 8.84 (s, 1H), 8.18 (d, J=7.5 Hz, 1H), 7.65 (d,J=8.0 Hz, 1H), 7.43 (app t, J=8.0 Hz, 1H), 4.62-4.52 (m, 1H), 3.59 (t,J=7.0 Hz, 1H), 3.15-3.06 (m, 3H), 2.64-2.50 (m, 6H), 2.35-2.28 (m, 1H),2.24 (s, 3H), 2.16-1.88 (m, 7H), 1.83-1.74 (m, 2H), 1.56-1.40 (m, 2H),1.17-1.07 (m, 2H); MS (ESI+) m/z 397 (M+H).

Step E: To solution of the carboxamide product from Step D (0.30 mg,0.75 mmol) in dichloromethane (5 mL) was added HCl (1 M solution inethyl ether, 2.26 mL, 2.26 mmol). The mixture was stirred at roomtemperature for 15 mins, and then the solvent was removed under vacuum.The amorphous solid was lyophilized from water (2 mL) containing a fewdrops of acetonitrile to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1-methylpiperidin-2yl)benzoxazole-4-carboxamidehydrochloride (209 mg, 94%) as an off-white solid and as a mixture ofenantiomers: ¹H NMR (500 MHz, DMSO-d₆) δ 12.50 (s, 0.8H), 12.35 (s,0.2H), 10.62 (s, 0.2H), 9.72 (s, 0.8H), 8.98 (d, J=5.5 Hz, 0.2H), 8.82(d, J=5.5 Hz, 0.6H), 8.04 (app q, J=8.5 Hz, 2H), 7.64 (app t, J=8.5 Hz,1H), 5.00-4.88 (m, 1H), 4.82-4.72 (m, 0.8H), 4.43-4.36 (m, 0.2H), 3.63(d, J=9.0 Hz, 1.5H), 3.58-3.50 (m, 1.5H), 3.46-3.38 (m, 0.2H), 3.28-3.19(m, 0.8H), 2.87-2.80 (m, 3H), 2.77-2.68 (m, 3H), 2.68-2.57 (m, 1H),2.55-2.42 (m, 2H), 2.35-2.03 (m, 7H), 1.94-1.84 (m, 3H), 1.72-1.60 (m,1H), 1.58-1.43 (m, 3H); MS (ESI+) m/z 397 (M+H); HPLC >99% (AUC),t_(R)=12.84 min. Anal. Calcd for C₂₃H₃₂N₄O₂.2HCl.H₂O: C, 56.67; H, 7.44;N, 11.49. Found: C, 56.98; H, 7.67; N, 11.39.

Example 34 Preparation ofEndo-N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-methylbenzoxazole-4-carboxamide

Step A: To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (0.35g, 1.50 mmol) and acetyl chloride (0.11 mL, 1.50 mmol) indichloromethane (10 mL) was added triethylamine (0.84 mL, 6.0 mmol)dropwise, then the reaction mixture was stirred at room temperature for12 h. The reaction mixture was diluted with dichloromethane, and thenwashed with 2 N HCl. The aqueous layer was extracted withdichloromethane. The combined organic layers were washed with brine,dried (Na₂SO₄), filtered and concentrated. The crude product wasdissolved in toluene (10 mL) and the solution was treated withp-toluenesulfonic acid monohydrate (263 mg, 1.38 mmol). The reactionmixture was then heated to reflux for 1.5 h. The reaction was cooled toroom temperature, poured into water and extracted with ethyl acetate.The organic layer was separated then washed with water, brine, dried(Na₂SO₄), filtered and concentrated. The crude product was purified bycolumn chromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) toafford 2-methylbenzoxazole-4-carboxylic acid (0.17 g, 64%) as anoff-white solid: MS (ESI+) m/z 178 (M+H).

Step B: A mixture of 2-methylbenzoxazole-4-carboxylic acid from Step A(75 mg, 0.42 mmol), endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (95 mg, 0.42 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg,0.84 mmol) and 1-hydroxybenzotriazole (114 mg, 0.84 mmol) in DMF (4 mL)was stirred at room temperature for 5 min, then triethylamine (0.22 mL,1.68 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 12 h. The mixture was diluted with dichloromethane (20mL), then washed with a saturated solution of sodium bicarbonate (10mL). The aqueous layer was further extracted with dichloromethane (3×15mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 89:10:1 dichloromethane/methanol/concentrated ammoniumhydroxide) to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-methylbenzoxazole-4-carboxamide(40 mg, 30%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.84 (d, J=6.0Hz, 1H), 8.16 (dd, J=7.5, 1.0 Hz, 1H), 7.58 (dd, J=7.5, 1.0 Hz, 1H),7.39 (t, J=8.0 Hz, 1H), 4.64-4.55 (m, 1H), 3.12 (d, J=10.5 Hz, 2H), 2.71(s, 3H), 2.65-2.55 (m, 2H), 2.53 (s, 3H), 2.12-1.95 (m, 3H), 1.60-1.52(m, 1H), 1.45 (t, J=10.5 Hz, 2H), 1.12 (d, J=12.5 Hz, 2H); MS (ESI+) m/z314 (M+H); HPLC 98.0% (AUC), t_(R)=11.78 min.

Example 35 Preparation of(S)—N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-methylbenzoxazole-4-carboxamide

A mixture of 2-methylbenzoxazole-4-carboxylic acid (75 mg, 0.42 mmol),(S)-(−)-3-aminoquinuclidine dihydrochloride (84 mg, 0.42 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg,0.84 mmol) and 1-hydroxybenzotriazole (114 mg, 0.84 mmol) in DMF (4 mL)was stirred at room temperature for 5 min, then triethylamine (0.22 mL,1.68 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 12 h. The mixture was diluted with dichloromethane (20mL), then washed with a saturated solution of sodium bicarbonate (10mL). The aqueous layer was further extracted with dichloromethane (3×15mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude material was purified by column chromatography(silica gel, 89:10:1 dichloromethane/methanol/concentrated ammoniumhydroxide) to afford(S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-methylbenzoxazole-4-carboxamide(39 mg, 33%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.37 (d, J=7.0Hz, 1H), 8.14 (dd, J=7.5, 1.0 Hz, 1H), 7.60 (dd, J=8.0, 2.0 Hz, 1H),7.41 (t, J=8.0 Hz, 1H), 4.28-4.23 (m, 1H), 3.47 (ddd, J=11.5, 9.5, 2.0Hz, 1H), 3.08-2.85 (m, 4H), 2.76 (dd, J=14.0, 4.5 Hz, 1H), 2.70 (s, 3H),2.13-2.07 (m, 1H), 2.02-1.93 (m, 1H), 1.78-1.70 (m, 2H), 1.60-1.51 (m,1H); MS (ESI+) m/z 286 (M+H); HPLC >99% (AUC), t_(R)=11.14 min.

Example 36 Preparation ofN-(9-Azabicyclo[3.3.1]non-3-yl)-2-cyclopropylbenzoxazole-4-carboxamideHydrochloride

Step A: To a solution ofendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-cyclopropylbenzoxazole-4-carboxamide(260 mg, 0.766 mmol) in THF (2 mL) was added a solution of sodiumhydroxide (0.60 g, 15 mmol) in water (10 mL) at 0° C., followed by asolution of KMnO₄ (0.60 g, 3.8 mmol) in water (30 mL). The mixture wasstirred at 0° C. for 1 h, and then was quenched with a saturatedsolution of sodium bicarbonate and extracted with methylene chloride.The combined organic layers were washed with brine, dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:9:1 dichloromethane/methanol/concentratedammonium hydroxide) to afford the desired secondary amine (37 mg, 15%)as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.90 (d, J=7.5 Hz, 1H), 8.11(dd, J=7.5, 1.0 Hz, 1H), 7.53 (dd, J=7.5, 1.0 Hz, 1H), 7.34 (t, J=7.5Hz, 1H), 4.32-4.23 (m, 1H), 3.45-3.40 (m, 2H), 2.44-2.28 (m, 3H),2.05-1.70 (m, 4H), 1.60-1.25 (m, 9H); MS (ESI+) m/z 326 (M+H).

Step B: Hydrogen chloride in diethyl ether (1.0 M, 0.11 mL, 0.11 mmol)was added dropwise to a solution of the amine from Step A (35 mg, 0.11mmol) in methylene chloride (1 mL) at 0° C. The mixture was stirred for2 min, and then was diluted with diethyl ether (30 mL). The white solidwas filtered, washed with diethyl ether, and dried under vacuumovernight to affordN-(9-azabicyclo[3.3.1]non-3-yl)-2-cyclopropylbenzoxazole-4-carboxamidehydrochloride (30 mg, 77%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ8.83-8.49 (m, 3H), 7.88-7.84 (m, 2H), 7.44 (t, J=7.5 Hz, 1H), 4.44-4.35(m, 1H), 3.85-3.80 (m, 2H), 2.50-2.40 (m, 3H), 2.12-1.85 (m, 3H),1.65-1.23 (m, 9H); MS (ESI+) m/z 326 (M+H); HPLC >99% (AUC), t_(R)=11.80min.

Example 37 Preparation ofEndo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-tert-butylbenzoxazole-7-carboxamide Hydrochloride

Step A: A mixture of pivaldehyde (1.65 mL, 15.4 mmol), methyl3-amino-2-hydroxybenzoate (501 mg, 3.0 mmol) and Darco KB-B (375 mg) inxylenes (8 mL) was heated under an oxygen atmosphere at 120° C. for 12h. The reaction mixture was cooled to room temperature, filtered througha celite pad. The filtrate was concentrated and the crude material waspurified by column chromatography (silica gel, 7:3 hexanes/ethylacetate) to afford the desired methyl2-tert-butylbenzoxazole-7-carboxylate (417 mg, 60%) as a light orangeoil: ¹H NMR (500 MHz, CDCl₃) δ 7.94 (dd, J=7.8, 0.9 Hz, 1H), 7.88 (dd,J=7.8, 0.9 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 4.01 (s, 3H), 1.54 (s, 9H);MS (ESI+) m/z 234 (M+H).

Step B: A mixture of methyl 2-tert-butylbenzoxazole-7-carboxylate (0.41g, 1.77 mmol), lithium hydroxide monohydrate (222 mg, 5.30 mmol) andtetrahydrofuran/water (5:1, 6 mL) was stirred at room temperature for 17h. The reaction mixture was cooled to 0° C., adjusted to pH 2 using 1 NHCl, and then extracted with dichloromethane (2×200 mL). The combinedorganic phase was washed with brine (2×50 mL), dried (Na₂SO₄), filteredand concentrated to afford the desired2-tert-butylbenzoxazole-7-carboxylic acid (336 mg, 86%) as a pink solid:¹H NMR (300 MHz, DMSO-d₆) δ 13.20 (br s, 1H), 7.95 (d, J=7.8 Hz, 1H),7.84 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 1.45 (s, 9H); MS (ESI+)m/z 220 (M+H).

Step C: A mixture of 2-tert-butylbenzoxazole-7-carboxylic (200 mg, 0.91mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (259mg, 1.14 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (348 mg, 1.82 mmol) and 1-hydroxybenzotriazole (246 mg,1.82 mmol) in DMF (5 mL) was stirred under nitrogen at room temperaturefor 10 min, and then triethylamine (0.51 mL, 3.64 mmol) was added. Theresulting reaction mixture was stirred at room temperature for 17 h. Thereaction was quenched with saturated aqueous sodium bicarbonate (10 mL),and then extracted with ethyl acetate (2×100 mL). The combined organicphase was washed with water (1×50 mL), brine (1×50 mL) dried (Na₂SO₄),filtered and concentrated. The crude material was purified by columnchromatography (silica gel, 90:6:1 dichloromethane/methanol/concentratedammonium hydroxide) to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-tert-butylbenzoxazole-7-carboxamide (266 mg, 82%) as a white solid: ¹H NMR (500MHz, CDCl₃) δ 8.05 (d, J=7.8 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.41 (t,J=7.8 Hz, 1H), 6.92 (d, J=6.2 Hz, 1H), 4.65-4.54 (m, 1H), 3.15 (d, J=9.1Hz, 2H), 2.67-2.60 (m, 2H), 2.55 (s, 3H), 2.10-1.95 (m, 3H), 1.65-1.58(m, 1H), 1.55 (s, 9H), 1.45-1.35 (m, 2H), 1.18-1.10 (m, 2H); MS (ESI+)m/z 356 (M+H).

Step D: To an ice cold solution ofendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-tert-butylbenzoxazole-7-carboxamide (141 mg, 0.39 mmol) in methanol (2 mL) anddichloromethane (2 mL) was slowly added a solution of HCl (1 N indiethyl ether, 0.39 mL, 0.39 mmol). The reaction mixture was dilutedwith diethyl ether (250 mL). The resulting solid was filtered and washedwith diethyl ether (200 mL) to afford a white solid. The solid waslyophilized from water (4 mL) and acetonitrile (2 mL) to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-tert-butylbenzoxazole-7-carboxamide hydrochloride (160 mg, 100%) as a white solid:¹H NMR (500 MHz, DMSO-d₆) δ 10.18 (br s, 0.25H), 9.44 (br s, 0.75H),8.47 (d, J=7.4 Hz, 0.25H), 8.37 (d, J=7.4, Hz, 0.75H), 7.87-7.84 (m,1H), 7.63-7.68 (m, 1H), 7.46-7.42 (m, 1H), 4.65-4.55 (m, 0.75H),4.38-4.30 (m, 0.25H), 3.65-3.56 (m, 2H), 3.55-3.38 (m, 2H), 2.84-2.80(m, 3H), 2.64-2.60 (m, 1H), 2.20-2.02 (m, 3H), 1.85-1.75 (m, 3H),1.60-1.52 (m, 1H), 1.46 (s, 9H); MS (ESI+) m/z 356 (M+H); HPLC 93.4%(AUC), t_(R)=9.70 min. Anal. Calcd for C₂₁H₂₉N₃O₂.HCl: C, 58.31; H,7.86; N, 9.71; Cl, 10.24. Found: C, 58.29; H, 7.79; N, 9.71; Cl, 10.29.

Example 38 Preparation of(S)—N-(Azabicyclo[2.2.2]oct-3-yl)-2-(morpholinomethyl)benzoxazole-4-carboxamideHydrochloride

Step A: To an ice-cooled suspension of 2-amino-3-hydroxybenzoic acidhydrobromide (3.0 g, 12.8 mmol) in toluene (30 mL) and methanol (30 mL)was added (trimethylsilyl)diazomethane (16.0 mL, 2 M solution in ethylether, 32.0 mmol) slowly, then the mixture was stirred at 0° C. for 20min. Acetic acid (5 mL) was added into the reaction mixture at 0° C.,then the mixture was stirred at room temperature for 0.5 h. The reactionmixture was concentrated under reduced pressure, and then the crude wasdissolved in ethyl acetate and washed with a saturated solution ofsodium bicarbonate and brine. The organic layer was dried (Na₂SO₄),filtered and concentrated under reduced pressure. The crude product waspurified by column chromatography (silica gel, 1:1 hexanes/ethylacetate) to afford the desired product (2.04 g, 95%) as a light brownsolid: ¹H NMR (500 MHz, CDCl₃) δ 7.48 (dd, J=8.0, 1.5 Hz, 1H), 6.81 (dd,J=7.5, 1.5 Hz, 1H), 6.50 (t, J=8.0 Hz, 1H), 5.80 (br s, 2H), 3.87 (s,3H); MS (ESI+) m/z 168 (M+H).

Step B: A mixture of methyl 2-amino-3-hydroxybenzoate (3.5 g, 20.70mmol) and 2-chloro-1,1,1-trimethoxyethane (3.0 mL, 22.06 mmol) inethanol (30 mL) was stirred under reflux for 6 h. The reaction mixturewas cooled to ambient temperature and the solvent volume was reducedunder reduced pressure approximately to ⅔ of initial volume. Theprecipitate formed was filtered, washed with ether (3×10 mL), and driedunder vacuum to afford methyl 2-(chloromethyl)benzoxazole-4-carboxylate(3.1 g, 66%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.05 (dd,J=8.0, 1.0 Hz, 1H), 7.78 (dd, J=9.0, 1.0 Hz 1H), 7.47 (t, J=5.0 Hz, 1H),4.84 (s, 2H), 4.04 (s, 3H); (APCI+) m/z 226 (M+H).

Step C: A mixture of the product from Step B (281 mg, 1.24 mmol) andmorpholine (2.0 mL, 23 mmol) in DMF (10 mL) was stirred at ambienttemperature for 16 h. The solvent was removed under reduced pressure andthe residue was treated with ethyl acetate (10 mL). The formedprecipitate was filtered off and mother liquor was concentrated underreduced pressure to afford methyl2-(morpholinomethyl)benzoxazole-4-carboxylate (333 mg, 97%) as a yellowsolid: ¹H NMR (300 MHz, CDCl₃) δ 8.01 (dd, J=9.0, 1.0 Hz, 1H), 7.74 (dd,J=9.0, 1.0 Hz, 1H), 6.40 (t, J=7.8 Hz, 1H), 4.02 (s, 2H), 3.97 (s, 3H),3.78-3.74 (m, 4H), 2.69-2.65 (m, 4H); MS (ESI+) m/z 277 (M+H).

Step D: A mixture of the product from Step C (333 mg, 1.20 mmol) andlithium iodide (642 mg, 4.80 mmol) in pyridine (15 mL) was stirred at120° C. for 16 h. The solvent was removed under reduced pressure toafford a black powder (0.9 g). Analysis by LC-MS indicated only one mainproduct with (APCI+) m/z 273 (M+H), consistent with desired acid. Theobtained powder was dissolved in anhydrous DMF (15 mL) and the obtainedsolution was elaborated into next step without further purification.(S)-(−)-3-Aminoquinuclidine dihydrochloride (140 mg, 0.72 mmol) and HBTU(224 mg, 0.58 mmol) were added to the obtained solution (7.5 mL) and themixture was stirred under nitrogen at room temperature for 10 min.Triethylamine (0.15 mL, 1.2 mmol) was added and the resulting reactionmixture was stirred at room overnight. The reaction was quenched withsaturated aqueous sodium bicarbonate (50 mL), and then extracted withdichloromethane (2×100 mL). The combined organic phase was washed withbrine (2×100 mL), water (2×100 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The crude material was purified bycolumn chromatography (silica gel, 10:1:0.1dichloromethane/methanol/concentrated ammonium hydroxide) to afford(S)—N-(quinulidin-8-yl)-2-(morpholinomethyl)benzoxazole-4-carboxamide(62 mg, 29%) as a yellow solid: ¹H NMR (300 MHz, CDC₃) δ 9.34 (d, J=6.0Hz, 1H), 8.17 (dd, J=7.8, 1.0 Hz, 1H), 7.68 (dd, J=9.0, 1.0 Hz, 1H),7.47 (t, J=8.1 Hz, 1H), 4.48-4.35 (m, 1H) 3.90 (s, 2H), 3.79-3.72 (m,4H), 3.57-3.45 (m, 1H), 3.10-3.00 (m, 1H), 2.98-2.92 (m, 2H), 2.85-2.74(m, 1H), 2.71-2.68 (m, 4H), 2.20-2.08 (m, 1H), 2.07-1.92 (m, 2H),1.84-1.72 (m, 2H), 1.68-1.52 (m, 1H); MS (APCI+) m/z 371 (M+H).

Step E: To a solution of the product from Step D (30 mg, 0.07 mmol) inmethanol (2 mL) was slowly added a solution of HCl (1.25 N in methanol,0.12 mL, 0.14 mmol). The reaction mixture was stirred for 5 minutes atambient temperature and then concentrated under reduced pressure. Theresulting residue was lyophilized from water (5 mL) to afford(S)—N-(quinulidin-8-yl)-2-(morpholinomethyl)benzoxazole-4-carboxamidehydrochloride (26 mg, 82%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ10.14 (s, 1H), 9.05 (s, 1H), 8.03 (d, J=8.1, 1H), 7.95 (d, J=7.8 Hz,1H), 7.61 (t, J=8.0 Hz, 1H), 4.35 (s, 1H), 3.92-3.82 (m, 4H), 3.74-3.70(m, 2H), 3.60-3.40 (m, 6H), 3.25-3.23 (m, 4H), 2.28-2.26 (m, 1H),2.20-2.12 (m, 1H), 1.97-1.94 (m, 2H), 1.90-1.80 (m, 1H); MS (ESI) m/z371 (M+H); HPLC 98.0% (AUC), t_(R)=9.91 min.

Example 39 Preparation ofEndo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(morpholinomethyl)benzoxazole-4-carboxamideHydrochloride

Step A: Endo-N-3-amino-(9-methyl-9-azabicyclo[3.3.1]nonanedihydrochloride (160 mg, 0.72 mmol) and HBTU (224 mg, 0.58 mmol) wereadded to the solution (7.5 mL) of crude2-(morpholinomethyl)benzoxazole-4-carboxylic acid. The mixture wasstirred under nitrogen at ambient temperature for 10 min, and thentriethylamine (0.15 mL, 1.2 mmol) was added. The resulting reactionmixture was stirred at ambient temperature for 16 h. The reaction wasquenched with saturated aqueous sodium bicarbonate (50 mL), and thenextracted with dichloromethane (2×100 mL). The combined organic phasewas washed with brine (2×100 mL), water (2×100 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The crude materialwas purified by column chromatography (silica gel, 10:1:0.1dichloromethane/methanol/concentrated ammonium hydroxide) to afford(endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(morpholinomethyl)benzoxazole-4-carboxamide(90 mg, 39%) as a yellow powder; MS (APCI) m/z 399 (M+H).

Step B: To a solution of the product from Step A (88 mg, 0.22 mmol) inmethanol (2 mL) was slowly added a solution of HCl (1.25 N in methanol,0.35 mL, 0.44 mmol). The reaction mixture was stirred for 10 min atambient temperature and concentrated under reduced pressure. Theresulting residue was lyophilized from water (5 mL) to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(morpholinomethyl)benzoxazole-4-carboxamidehydrochloride (65 mg, 68%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ10.45 (s, 0.3H), 9.63 (s, 0.7H), 9.06 (br s, 0.3H), 8.84 (d, J=6.0 Hz,0.7H), 8.02-7.99 (m, 1H), 7.97-7.94 (m, 1H), 7.58 (t, J=7.5 Hz, 1H),4.72-4.5.6 (m, 2H), 4.40-4.38 (m, 1H), 4.06-3.70 (m, 4H), 3.65 (d, J=9.5Hz, 2H), 3.57 (d, J=6.5 Hz, 1H), 3.52-3.30 (m, 4H), 2.87-2.82 (m, 3H),2.71-2.61 (m, 1H), 2.54 (s, 1H), 2.32-2.20 (m, 1.5H), 2.17-2.08 (m,1.5H), 1.98 (s, 1H), 187-1.70 (m, 1H), 1.54-1.46 (m, 2H); MS (ESI) m/z399 (M+H); HPLC 98.14% (AUC), t_(R)=9.90 min.

Example 40 Preparation of(S)—N-(Azabicylco[2.2.2]oct-3-yl)-2-(diethylaminomethyl)benzoxazole-4-carboxamideHydrochloride

Step A: A mixture of methyl 2-(chloromethyl)benzoxazole-4-carboxylate(267 mg, 1.18 mmol) and diethylamine (2.0 mL, 27.4 mmol) in THF (15 mL)was stirred at ambient temperature overnight. The solvent was removedunder reduced pressure and the residue was purified by columnchromatography (silica gel, 10:1:0.1dichloromethane/methanol/concentrated ammonium hydroxide), followed bypurification by preparative TLC (silica gel, 10:1:0.1dichloromethane/methanol/concentrated ammonium hydroxide) to affordmethyl 2-(diethylaminomethyl)benzoxazole-4-carboxylate (200 mg, 64%) asa yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 7.99 (dd, J=9.0, 1.0 Hz, 1H),7.74 (dd, J=9.0, 1.0 (1H), 6.40 (t, J=8.1 Hz, 1H), 4.09 (s, 2H), 4.04(s, 3H), 2.74-2.69 (m, 4H), 1.13 (t, J=6.6 Hz, 1H); MS (ESI+) m/z 263(M+H).

Step B: A mixture of the product from Step A (200 mg, 0.7 mmol) andlithium iodide (398 mg, 2.97 mmol) in pyridine (15 mL) was stirred at125° C. overnight. The solvent was removed under reduced pressure toafford a brown oil (0.7 g). Analysis by LC-MS indicated only one mainproduct with (APCI+) m/z 249 (M+H), consistent with desired acid. Theobtained oil was dissolved in anhydrous DMF (15 mL) and the obtainedsolution was elaborated into the next step without further purification.(S)-(−)-3-Aminoquinuclidine dihydrochloride (120 mg, 0.60 mmol) and HBTU(305 mg, 0.80 mmol) were added to the obtained solution (10 mL) and themixture was stirred under nitrogen at room temperature for 10 min, andthen triethylamine (0.30 mL, 2.16 mmol) was added. The resultingreaction mixture was stirred at ambient temperature overnight. Thereaction was quenched with saturated aqueous sodium bicarbonate (50 mL),and then extracted with dichloromethane (2×100 mL). The combined organicphase was washed with brine (2×100 mL) water (2×100 mL), dried (Na₂SO₄),filtered and concentrated under reduced pressure. The crude material waspurified by column chromatography (silica gel, 10:1:0.1dichloromethane/methanol/concentrated ammonium hydroxide), followed bypurification by preparative TLC (silica gel, 10:1:0.1dichloromethane/methanol/concentrated ammonium hydroxide) to afford(S)—N-(quinulidin-8-yl)-2-(diethylaminomethyl)benzoxazole-4-carboxamide(63 mg, 29%) as a yellow solid: MS (APCI+) m/z 357 (M+H).

Step C: To a solution of the product from Step B (52 mg, 0.14 mmol) inmethanol (2 mL) was slowly added a solution of HCl (1.25 N in methanol,0.32 mL, 0.40 mmol). The reaction mixture was stirred for 10 minutes atambient temperature and concentrated under reduced pressure. Theresulting residue was lyophilized from water (5 mL) to afford(S)—N-(quinulidin-8-yl)-2-(diethylaminomethyl)benzoxazole-4-carboxamidehydrochloride (57 mg, 65%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ10.71 (s, 1H), 10.14 (s, 1H), 8.96 (d, J=5.1 Hz, 1H), 8.06 (d, J=8.0 Hz,1H), 7.65-7.61 (m, 1H), 4.90 (s, 2H), 4.64 (s, 1H), 3.72 (d, J=10.8 Hz,1H), 3.54-3.48 (m, 4H), 3.44-3.27 (m, 8H), 3.24 (d, J=7.2 Hz, 3H),2.31-2.26 (m, 1H), 2.17-2.09 (m, 1H), 1.97-1.94 (m, 2H), 1.89-1.71 (m,1H), 1.35 (s, 3H); MS (ESI) m/z 357 (M+H); HPLC 98.50% (AUC), t_(R)=9.73min.

Example 41 Preparation ofEndo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(diethylaminomethyl)benzoxazole-4-carboxamideHydrochloride

Step A: A mixture of methyl 2-amino-3-hydroxybenzoate (3.5 g, 20.70mmol) and 2-chloro-1,1,1-trimethoxyethane (3.0 mL, 22.06 mmol) inethanol (30 mL) was stirred under reflux for 6 h. The reaction mixturewas cooled to ambient temperature and the solvent volume was reducedunder reduced pressure approximately to ⅔ of initial volume. Theprecipitate formed was filtered, washed with ether (3×10 mL) and driedto afford methyl 2-(chloromethyl)benzoxazole-4-carboxylate (3.1 g, 66%)as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.05 (dd, J=8.0, 1.0 Hz,1H), 7.78 (dd, J=9.0, 1.0 Hz 1H), 7.47 (t, J=5.0 Hz, 1H), 4.84 (s, 2H),4.04 (s, 3H); (APCI+) m/z 226 (M+H).

Step B: A mixture of methyl 2-(chloromethyl)benzoxazole-4-carboxylate(267 mg, 1.18 mmol) and diethylamine (2.0 mL, 27.4 mmol) in THF (15 mL)was stirred at ambient temperature overnight The solvent was removedunder reduced pressure and the residue was purified by columnchromatography (silica gel, 10:1:0.1dichloromethane/methanol/concentrated ammonium hydroxide), followed bypurification by preparative TLC (silica gel, 10:1:0.1dichloromethane/methanol/concentrated ammonium hydroxide) to affordmethyl 2-(diethylaminomethyl)benzoxazole-4-carboxylate (200 mg, 64%) asa yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 7.99 (dd, J=9.0, 1.0 Hz, 1H),7.74 (dd, J=9.0, 1.0 (1H), 6.40 (t, J=8.1 Hz, 1H), 4.09 (s, 2H), 4.04(s, 3H), 2.74-2.69 (m, 4H), 1.13 (t, J=6.6 Hz, 1H); MS (ESI+) m/z 263(M+H).

Step C: A mixture of methyl2-((diethylamino)methyl)benzoxazole-4-carboxylic acid (200 mg, 0.7 mmol)and lithium iodide (398 mg, 2.97 mmol) in pyridine (15 mL) was stirredat 125° C. overnight. The solvent was removed under reduced pressure toafford a brown oil (0.7 g). Analysis by LC-MS indicated only one mainproduct with (APCI+) m/z 249 (M+H), consistent with the desired acid.The obtained oil was dissolved in anhydrous DMF (15 mL) and the obtainedsolution was elaborated into the next step without further purification.1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (90 mg, 0.5mmol), 1-hydroxybenzotriazole (70 mg, 0.5 mmol), andendo-N-3-amino-(9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (57mg, 0.25 mmol) were added to the obtained solution (5 mL) and themixture was stirred under nitrogen at room temperature for 10 min, andthen triethylamine (0.15 mL, 1.08 mmol) was added. The resultingreaction mixture was stirred at ambient temperature for 16 h. Thereaction was quenched with saturated aqueous sodium bicarbonate solution(50 mL), and then extracted with dichloromethane (2×100 mL). Thecombined organic phase was washed with brine (2×100 mL) water (2×100mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure.The crude material was purified by column chromatography (silica gel,10:1:0.1 dichloromethane/methanol/concentrated ammonium hydroxide),followed by purification by preparative TLC (silica gel, 10:1:0.1dichloromethane/methanol/concentrated ammonium hydroxide) to affordendo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(diethylaminomethyl)benzoxazole-4-carboxamide(43 mg, 55%) as a clear oil: MS (APCI+) m/z 385 (M+H).

Step D: To a solution of the product from Step C (43 mg, 0.11 mmol) inmethanol (2 mL) was slowly added a solution of hydrochloric acid (1.25 Nin methanol, 0.16 mL, 0.20 mmol). The reaction mixture was stirred for10 min at ambient temperature and then concentrated under reducedpressure. The resulting residue was lyophilized from water (5 mL) toaffordendo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-(diethylaminomethyl)benzoxazole-4-carboxamidehydrochloride (37 mg, 73%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ10.47 (s, 0.2H), 9.55 (s, 0.8H), 8.84 (s, 0.2H); 8.76 (d, J=7.5 Hz,0.8H), 8.06-8.03 (m, 1H), 8.00-7.96 (m, 1H), 7.66-7.59 (m, 1H),4.88-4.85 (m, 2H), 4.79-4.70 (m, 0.8H), 4.43-4.38 (m, 0.2H), 3.67-3.64(m, 1.5H), 3.60-3.58 (m, 0.5H), 3.37-3.34 (m, 8H), 2.69-2.62 (m, 0.5H),2.39-2.28 (m, 1H), 2.23-2.21 (m, 0.5H), 2.12-1.99 (m, 3H), 1.91-1.88 (m,0.5H), 1.81-1.78 (0.5H), 1.52-1.49 (m, 1H), 1.46-1.42 (m, 2H), 1.38-1.35(m, 6H); MS (ESI) m/z 385 (M+H); HPLC 98.07% (AUC), t_(R)=10.42 min.

Example 42 Preparation ofEndo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((4S,5R/4R,5S)-3,5-dimethyl-2-oxo-oxazolidin-4-yl)benzoxazole-4-carboxamide

Step A: To a solution of (2S,3R/2R,3S)-methyl3-hydroxy-2-(methylamino)butanoate¹ (600 mg, 4.08 mmol) andtriethylamine (1.71 mL, 12.27 mmol) in dichloromethane (30 mL) was addeda solution of triphosgene (424 mg, 1.43 mmol) in dichloromethane (10mL). The reaction was stirred at ambient temperature for 8 h thenpartitioned with 1 N HCl (20 mL). The organic layer was dried overNa₂SO₄ and concentrated under reduced pressure. The crude material wasdissolved in methanol (10 mL) and treated with a solution of NaOH (326mg, 8.15 mmol) in water (2 mL). The reaction mixture was stirred atambient temperature for 14 h, then 2 N HCl added until the mixtureattained pH 5. The reaction mixture was concentrated under reducedpressure and the residue was lyophilized. The resulting solid was heatedwith acetonitrile (50 mL) at 60° C. and insoluble inorganic saltsremoved by filtration. The filtrate was concentrated under reducedpressure to afford(4S,5R/4R,5S)-3,5-dimethyl-2-oxo-oxazolidine-4-carboxylic acid as acolorless oil (410 mg, 63%): ¹H NMR (300 MHz, CD₃OD) δ 4.48-4.57 (m,1H), 3.84 (d, J=5.7 Hz, 1H), 2.90 (s, 3H), 1.47 (d, J=6.3 Hz, 3H). 1(2S,3R/2R,3S)-methyl 3-hydroxy-2-(methylamino)butanoate was preparedaccording to a literature procedure: Beulshausen et al. Liebigs Ann.Chem. 1992, 523-526.

Step B: To a solution of(4S,5R/4R,5S)-3,5-dimethyl-2-oxo-oxazolidine-4-carboxylic acid (200 mg,1.26 mmol) in DMF (0.5 mL) and THF (4.5 mL) at 0° C. was added oxalylchloride (123 μL, 1.38 mmol). The reaction was stirred at ambienttemperature for 2 h then concentrated under reduced pressure. Theresidue was dissolved in THF (5 mL) and methyl 2-amino-3-hydroxybenzoate(420 mg, 2.51 mmol) added followed by pyridine (255 μL, 3.15 mmol). Thereaction mixture was stirred at ambient temperature for 60 h thenpartitioned with ethyl acetate (50 mL) and 0.5 M citric acid (20 mL).The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (20 to 60% ethyl acetate/hexanes) to afford methyl2-((4S,5R/4R,5S)-3,5-dimethyl-2-oxo-oxazolidine-4-carboxamido)-3-hydroxybenzoateas a yellow oil (195 mg, 50%): ¹H NMR (300 MHz, CDCl₃) δ 7.60-7.65 (m,1H), 7.20-7.27 (m, 2H), 4.60-4.72 (m, 1H), 4.00-4.08 (m, 1H), 3.94 (s,3H), 3.03 (s, 3H), 1.60 (d, J=6.4 Hz, 3H).

Step C: To a solution of methyl2-((4S,5R/4R,5S)-3,5-dimethyl-2-oxo-oxazolidine-4-carboxamido)-3-hydroxybenzoate(226 mg, 0.73 mmol), triphenylphosphine (495 mg, 1.89 mmol) anddiisopropylethylamine (0.77 mL, 4.40 mmol) in dichloromethane (10 mL)was added hexachloroethane (434 mg, 1.83 mmol). The reaction mixture wasstirred at ambient temperature for 20 h then quenched with a saturatedsolution of ammonium chloride (4 mL). The mixture was partitioned withdichloromethane (30 mL) and water (20 mL). The organic layer was washedwith brine, dried (Na₂SO₄) and concentrated under reduced pressure. Thecrude material was purified by column chromatography (silica gel, EtOAc)to afford methyl2-((4S,5R/4R,5S)-3,5-dimethyl-2-oxo-oxazolidin-4-yl)benzoxazole-4-carboxylateas a yellow oil (180 mg, 85%): ¹H NMR (300 MHz, CDCl₃) δ 8.06 (dd,J=7.8, 1.0 Hz, 1H), 7.79 (dd, J=8.2, 1.0 Hz, 1H), 7.50 (t, J=8.0 Hz,1H), 4.80-4.88 (m, 1H), 4.76 (d, J=5.6 Hz, 1H), 4.03 (s, 3H), 2.91 (s,3H), 1.61 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 291 (M+H).

Step D: To a solution of methyl2-((4S,5R/4R,5S)-3,5-dimethyl-2-oxo-oxazolidin-4-yl)benzoxazole-4-carboxylate(180 mg, 0.62 mmol) in pyridine (7 mL) was added lithium iodide (831 mg,6.20 mmol). The reaction mixture was heated at 110° C. for 5 h andallowed to cool to ambient temperature before it was partiallyconcentrated under reduced pressure. The residue was partitioned withdichloromethane (30 mL) and 1 N HCl (20 mL). The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to afford crude2-((4S,5R/4R,5S)-3,5-dimethyl-2-oxo-oxazolidin-4-yl)benzoxazole-4-carboxylicacid as an orange oil. This material was directly elaborated withoutpurification.

Step E: To2-((4S,5R/4R,5S)-3,5-dimethyl-2-oxo-oxazolidin-4-yl)benzoxazole-4-carboxylicacid (171 mg. 0.62 mmol), in N,N-dimethylformamide (4 mL), was addedsuccessively endo-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-aminedihydrochloride (155 mg, 0.68 mmol), 1-hydroxybenzotriazole (168 mg,1.24 mmol), 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride(238 mg, 1.24 mmol) and triethylamine (261 μL, 1.86 mmol). The reactionwas stirred at ambient temperature for 16 h then partitioned with a 9:1mixture of dichloromethane and 2-propanol (100 mL) and water (100 mL).The phases were separated and the organic layer washed with brine beforedrying over Na₂SO₄. The organic layer was concentrated under reducedpressure and the residue purified by flash column chromatography (silicagel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) toaffordendo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-2-((4S,5R/4R,5S)-3,5-dimethyl-2-oxo-oxazolidin-4-yl)benzoxazole-4-carboxamide(108 mg, 42%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.54 (d,J=12.6 Hz, 1H), 8.26 (dd, J=7.7, 0.9 Hz, 1H), 7.70 (dd, J=8.2, 0.9 Hz,1H), 7.53 (t, J=8.0 Hz, 1H), 4.82-4.87 (m, 1H), 4.67 (d, J=5.7 Hz, 1H),4.52-4.61 (m, 1H), 3.10 (d, J=10.4 Hz, 2H), 3.00 (s, 3H), 2.53-2.62 (m,2H), 2.52 (s, 3H), 1.95-2.10 (m, 3H), 1.66 (d, J=6.3 Hz, 3H), 1.53-1.59(m, 1H), 1.37-1.44 (m, 2H), 1.08-1.14 (m, 2H); MS (ESI+) m/z 413 (M+H);HPLC >99% (AUC), t_(R) 12.7 min.

In other embodiments where R² is not hydrogen or halogen, the method ofpreparation of the foregoing is similar to those presented in U.S.Patent Application 2006/183769, the entire contents of which are hereinincorporated by reference. In situations where an inconsistency innomenclature between the foregoing application and the presentapplication may exist, the nomenclature and definitions of the presentapplication take precedence.

Compound Affinity for the Human 5-HT₃ Receptor (Assay A)

Compounds were tested by MDS Pharma Services—Taiwan Ltd., 158 Li—TheRoad, Peitou, Taipei, Taiwan 112 R.O.C. In order to evaluate therelative affinity of the various compounds for the human 5-HT₃ receptor,N1E-155 cell lines were developed to express the target protein. Forbinding, these cells were homogenized, centrifuged and washed withbuffer (20 mM HEPES, 150 mM NaCl, pH 7.4) then suspended in 0.5 mL ofbuffer and [³H]-GR65630 added at a concentration of 3.5×10⁻¹⁰ M. Aninitial single concentration of 10⁻⁷ M of the test compound was thenadded. Incubation was carried out at room temperature for 60 minutes at25° C. then was terminated by rapid removal of the incubation medium.Radioactivity was assessed using liquid scintillation spectrophotometryafter exposure to scintillation cocktail for at least three hours.Compounds displaying greater than 75% inhibition of radioligand bindingat 10⁻⁷ M were then resubmitted to the above protocol using thefollowing range of test compound concentrations: 10⁻⁹ M, 10⁻⁸ M, 3×10⁻⁸M, 10⁻⁷ M, 3×10⁻⁷ M and 10⁻⁶ M. Competition curves were then plotted andIC₅₀ determinations made using non-linear regression analysis. Ki valueswere then calculated from the Cheng-Prusoff equation. In all of theabove binding studies the non-specific determinant was MDL-72222 (1.0μM).

Compound Affinity for the Human 5-HT₃ Receptor (Assay B)

The relative affinity of the various compounds for the human 5-HT₃receptor was measured in a radioligand binding assay, using ascintillation proximity assay (SPA) format. Test compounds weredissolved to 10 mM in 100% DMSO, then serially diluted at 10× assayconcentrations in 100% DMSO in 96-well polypropylene plates and furtherdiluted to 4× assay concentrations with the assay buffer. Samples wereincubated in 50 mM Tris-HCl, pH 7.5, 3 mM MgCl₂, 1 mM EDTA and 10% DMSOwith 10 nM [9-methyl-3H]BRL-43694 (Perkin Elmer), 3 μg of human 5-HT₃receptor membranes (Perkin Elmer) and 0.5 mg/mL SPA beads (WGA PVT,Amersham Biosciences) in a final volume of 0.2 mL. Binding reactionswere set up in wells of PicoPlates-96 (Perkin Elmer) by addingconsecutively 50 μL of each competing compound or buffer, SPA beads, theradioligand and 5-HT₃ receptor membranes. After 60-min incubation atroom temperature on a Nutator mixer, plates were centrifuged for 15 minat 1,500 rpm, followed by incubation in the dark for 30 min.Radioactivity was counted in the TopCount microplate counter (PerkinElmer) for 5 min. Total binding control contained buffer only;nonspecific binding was determined in the presence of 30 μM MDL-72222.Specific binding was determined by subtracting nonspecific binding fromtotal binding. All experiments were performed in duplicate using tenconcentrations of a competing ligand, with ondansetron included as acontrol in every run. IC₅₀ values were determined from specific bindingdata using XLfit4.1 curve fitting software from IDBS Ltd. K_(i) valueswere then calculated from the Cheng-Prusoff equation.

Compound Affinity for the Mouse 5-HT₃Receptor (Assay C)

Compounds were tested by Novoscreen Biosciences Corporation, 7170Standard Drive, Hanover, Md. in a radioligand binding assay using themouse 5-HT₃ receptor derived from mouse neuroblastoma cells and[³H]-GR65630 (ligand). The non-specific binding determinant was MDL72222. Compounds were tested at a single concentration of 100 nM induplicate. Percent inhibition is reported. In order to evaluate therelative affinity of the various compounds for the 5-HT₃ receptor,N1E-155 cell lines were developed to express the target protein. Forbinding, these cells were homogenized, centrifuged and washed withbuffer (20 mM HEPES, 150 mM NaCl, pH 7.4) then suspended in 0.5 mL ofbuffer and [³H]-GR65630 added at a concentration of 3.5×10⁻¹⁰ M. Aninitial single concentration of 10⁻⁷ M of the test compound was thenadded. Incubation was carried out at room temperature for 60 minutes at25° C. then was terminated by rapid removal of the incubation medium.Radioactivity was assessed using liquid scintillation spectrophotometryafter exposure to scintillation cocktail for at least three hours.Compounds displaying greater than 75% inhibition of radioligand bindingat 10⁻⁷ M were then resubmitted to the above protocol using thefollowing range of test compound concentrations: 10⁻⁹M, 10⁻⁸M, 3×10⁻⁸ M,10⁻⁷ M, 3×10⁻⁷ M and 10⁻⁶ M. Competition curves were then plotted andIC₅₀ determinations made using non-linear regression analysis. Ki valueswere then calculated from the Cheng-Prusoff equation. In all of theabove binding studies the non-specific determinant was MDL-72222 (1.0μM).

Compound Affinity for the Human 5-HT₃Receptor (Assay D)

Compounds were tested by Cerep, Le Bois l'Evêque—B.P. 1-86600 Celle,L'Evescault, France in a radioligand binding assay using the humanrecombinant 5-HT₃ receptor (CHO cells, Hope, A. G., Peters, J. A.,Brown, A. M., Lambert, J. J. and Blackburn, T. P. Brit. J. Pharmacol.,1996, 118: 1237-1245) and [³H]BRL 43694 (ligand) with a 90 incubation at22° C. For the above studies, the non-specific binding determinant wasMDL 72222 (10 μM). The IC₅₀ values (concentration causing a half-maximalinhibition of control specific binding) and Hill coefficients weredetermined by non-linear regression analysis of the competition curvesusing Hill equation curve fitting. The inhibition constants (K_(i)) werecalculated from the Cheng Prusoff equation (K_(i)=IC₅₀/(1+(L/K_(D))),where L=concentration of radioligand in the assay, and K_(D)=affinity ofthe radioligand for the receptor).

In the table below, the assay in which the data were obtained is shown(as A, B. C, or D) along with the data.

Mouse % Inhibition @ Human 5HT₃ K_(i) Example Structure 100 nM (nM)  1

C 96.1 B 4.1  2

C 87.7 B 11  3

C 104.2 D 4.7  4

C 94.3 D 30  5

C 96.2 A 2.27  6

C 90.2  7

C 96.7 D 3.3  8

C 97.6 D 19  9

C 94.7 D 11 10

D 21 11

C 98.6 D 8.6 12

C 90.6 D 26 13

C 88.1 A 5.74 14

C 93.6 15

C 104.9 16

C 94.1 17

C 107.7 D 7 18

C 107.7 D 7 19

D 44 20

D 5.4 21

C 34.9 22

A 16.6 23

A 36.6 24

A 17.6 25

B 126 26

B 173 27

B 41 28

B 111 29

B 28 30

B 83 31

B 356 32

B 81.9 33

B 21.6 34

C 79 D 5.5 35

C 83 D 12 36

B 6.3 37

B 166 38

B 74% inhibition @ 10 μM 39

B 77.1 40

B 129 41

B 15.3 42

B 24.9

Bezold-Jarisch Assay in vivo. In order to demonstrate functionalantagonism of 5-HT₃ receptors, compounds 1 and 2 were evaluated fortheir ability to inhibit serotonin induced bradycardia in vivo in themouse [Saxena, P. R. and Lawang, A. A comparison of cardiovascular andsmooth muscle effects of 5-hydroxytryptamine and5-carboxamidotryptamine, a selective agonist of 5-HT₁ receptors. Arch.Int. Pharmacodyn. 277: 235-252, 1985]. Test substances and vehicle [2%Tween 80] were each administered orally (30 mg/kg) to a group of 5 maleor female CD-1(Crl.) mice each weighing 24±2 g. A dosing volume of 10mL/kg was used. Sixty minutes later, 5-HT (0.5 mg/kg IV)-inducedbradycardia was recorded in pentobarbital (80 mg/kg IP, given 10 minutesbefore 5-HT)-anesthetized animals. Compounds 1 and 2 exhibited 56% and80% inhibition, respectively.

The compounds of the invention may be administered orally or viainjection at a dose from 0.001 to 2500 mg/kg per day. The dose range foradult humans is generally from 0.005 mg to 10 g/day. Tablets or otherforms of presentation provided in discrete units may convenientlycontain an amount of compound of the invention which is effective atsuch dosage or as a multiple of the same, for instance, units containing5 mg to 500 mg, usually around 10 mg to 200 mg. The precise amount ofcompound administered to a patient will be the responsibility of theattendant physician. However, the dose employed will depend on a numberof factors, including the age and sex of the patient, the precisedisorder being treated, and its severity. Also, the route ofadministration may vary depending on the condition and its severity.

As used herein, and as would be understood by the person of skill in theart, the recitation of “a compound” is intended to include salts,solvates and inclusion complexes of that compound. The term “solvate”refers to a compound of Formula I in the solid state, wherein moleculesof a suitable solvent are incorporated in the crystal lattice. Asuitable solvent for therapeutic administration is physiologicallytolerable at the dosage administered. Examples of suitable solvents fortherapeutic administration are ethanol and water. When water is thesolvent, the solvate is referred to as a hydrate. In general, solvatesare formed by dissolving the compound in the appropriate solvent andisolating the solvate by cooling or using an antisolvent. The solvate istypically dried or azeotroped under ambient conditions. Inclusioncomplexes are described in Remington: The Science and Practice ofPharmacy 19th Ed. (1995) volume 1, page 176-177, which is incorporatedherein by reference. The most commonly employed inclusion complexes arethose with cyclodextrins, and all cyclodextrin complexes, natural andsynthetic, are specifically encompassed within the claims.

The term “pharmaceutically acceptable salt” refers to salts preparedfrom pharmaceutically acceptable non-toxic acids or bases includinginorganic acids and bases and organic acids and bases. When thecompounds of the present invention are basic, salts may be prepared frompharmaceutically acceptable non-toxic acids including inorganic andorganic acids. Suitable pharmaceutically acceptable acid addition saltsfor the compounds of the present invention include acetic,benzenesulfonic (besylate), benzoic, camphorsulfonic, citric,ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaricacid, p-toluenesulfonic, and the like. When the compounds contain anacidic side chain, suitable pharmaceutically acceptable base additionsalts for the compounds of the present invention include metallic saltsmade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc or organic salts made from lysine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine.

The term “preventing” as used herein refers to administering amedicament beforehand to forestall or obtund an attack. The person ofordinary skill in the medical art (to which the present method claimsare directed) recognizes that the term “prevent” is not an absoluteterm. In the medical art it is understood to refer to the prophylacticadministration of a drug to substantially diminish the likelihood orseriousness of a condition, and this is the sense intended herein.Indeed, the 2006 edition of the Physician's Desk Reference, which is thestandard text in the field, employs the term “prevent”, or “prevention”not less than 10 times in its description of the indications forpalonosetron.

The graphic representations of racemic, ambiscalemic and scalemic orenantiomerically pure compounds used herein are taken from Maehr J.Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denotethe absolute configuration of a chiral element; wavy lines indicatedisavowal of any stereochemical implication which the bond it representscould generate; solid and broken bold lines are geometric descriptorsindicating the relative configuration shown but denoting racemiccharacter; and wedge outlines and dotted or broken lines denoteenantiomerically pure compounds of indeterminate absolute configuration.A simple solid line implies nothing about stereochemistry. For example,a solid line is shown in the graphic for example 2 above, but thecompound of the example is actually a single enantiomer of the Sconfiguration and could have been accurately depicted as

While it may be possible for the compounds of formulas I and II to beadministered as the raw chemical, it is preferable to present them as apharmaceutical composition. According to a further aspect, the presentinvention provides a pharmaceutical composition comprising a compound offormula I or II or a pharmaceutically acceptable salt or solvatethereof, together with one or more pharmaceutically carriers thereof andoptionally one or more other therapeutic ingredients. The carrier(s)must be “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous andintraarticular), rectal and topical (including dermal, buccal,sublingual and intraocular) administration. The most suitable route maydepend upon the condition and disorder of the recipient. Theformulations may conveniently be presented in unit dosage form and maybe prepared by any of the methods well known in the art of pharmacy. Allmethods include the step of bringing into association a compound offormula I or II or a pharmaceutically acceptable salt or solvate thereof(“active ingredient”) with the carrier which constitutes one or moreaccessory ingredients. In general, the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both and then,if necessary, shaping the product into the desired formulation.Preferred unit dosage formulations are those containing an effectivedose or an appropriate fraction thereof, of the active ingredient.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide sustained, delayed or controlled releaseof the active ingredient therein.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions, which may containanti-oxidants, buffers, bacteriostats and solutes which render theformulation isotonic with the blood of the intended recipient.Formulations for parenteral administration also include aqueous andnon-aqueous sterile suspensions, which may include suspending agents andthickening agents. The formulations may be presented in unit-dose ofmulti-dose containers, for example sealed ampoules and vials, and may bestored in a freeze-dried (lyophilized) condition requiring only theaddition of a sterile liquid carrier, for example saline,phosphate-buffered saline (PBS) or the like, immediately prior to use.Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets of the kind previously described.

Formulations for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter or polyethylene glycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a basis such asgelatin and glycerin or sucrose and acacia.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Although the foregoing invention has been described in some detail forpurposes of illustration, it will be readily apparent to one skilled inthe art that changes and modifications may be made without departingfrom the scope of the invention described herein.

1. A method of treating irritable bowel syndrome, emesis, orpost-operative nausea or vomiting, which comprises administering to apatient in need of such treatment a therapeutically effective amount ofa compound of formula

wherein R¹, R² and R³ are independently selected from the groupconsisting of hydrogen, halogen, amino, alkylamino, dialkylamino,acylamino, morpholinyl, —O-loweralkyl, hydroxy, loweralkyl,fluoroloweralkyl, —O-lowerfluoroalkyl, methylenedioxy, ethylenedioxy,alkoxy-loweralkyl and hydroxyloweralkyl; R⁴ is a residue selected fromthe group consisting of: (i) a saturated nitrogen heterocycle ormethyl-substituted saturated nitrogen heterocycle, in which saidnitrogen is tertiary, said heterocycle containing at least one 5 or6-membered ring; and (ii) an imidazolylalkyl residue wherein theimidazole of said imidazolylalkyl is optionally substituted with up tothree groups chosen from halogen, (C₁-C₄)alkyl, substituted (C₁-C₄)alkyland NH₂; and R¹⁰ is selected from the group consisting of (i) hydrogen;(ii) (C₁-C₁₀)alkyl; (iii) substituted (C₁-C₁₀)alkyl; (iv) saturatedC-attached heterocyclyl; and (v) substituted, saturated C-attachedheterocyclyl.
 2. A method according to claim 1 wherein said disorder isirritable bowel syndrome.
 3. A method according to claim 1 for treatingemesis.
 4. A method according to claim 1 for treating post-operativenausea or vomiting.